TWI828027B - Pyrrolotriazine compounds as tam inhibitors - Google Patents

Abstract

This application relates to compounds of Formula I:

Description

Pyrrotriazine compounds as TAM inhibitors

This application relates to pyrrolotriazine inhibitors of TAM kinases, and in one embodiment to inhibitors of AXL and MER kinases, suitable for the treatment of conditions such as cancer, and to pharmaceutical compositions related thereto. .

Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion and migration.

The TAM subfamily consists of three RTKs, including Tyro3, AXL and Mer (Graham et al., 2014, Nature Reviews Cancer 14 , 769-785; Linger et al., 2008, Advances in Cancer Research 100 , 35-83). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands have been identified for TAM kinases, growth arrest-specific protein 6 (GAS6) and protein S (PROS1). GAS6 can bind and activate all three TAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al., 2014, Nature Reviews Cancer 14 , 769-785).

AXL (also known as UFO, ARK, JTK11, and TYRO7) was originally identified as a transforming gene in DNA from patients with chronic myelogenous leukemia (O'Bryan et al., 1991, Mol Cell Biol 11, 5016-5031 ; Graham et al., 2014 , Nature Reviews Cancer 14 , 769-785; Linger et al., 2008, Advances in Cancer Research 100 , 35-83). GAS6 binds AXL and induces subsequent autophosphorylation and activation of AXL tyrosine kinase. AXL activates several downstream signal transduction pathways, including PI3K-Akt, Raf-MAPK, and PLC-PKC (Feneyrolles et al., 2014, Molecular Cancer Therapeutics 13 , 2141-2148; Linger et al., 2008, Advances in Cancer Research 100 , 35-83).

MER (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was originally identified as a phosphoprotein from the lymphoblastoid-expressing gene repertoire (Graham et al., 1995, Oncogene 10 , 2349-2359; Graham et al., 2014 , Nature Reviews Cancer 14 , 769-785; Linger et al., 2008, Advances in Cancer Research 100 , 35-83). Both GAS6 and PROS1 can bind Mer and induce phosphorylation and activation of Mer kinase (Lew et al., 2014). Like AXL, MER activation also communicates downstream signaling pathways, including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Advances in Cancer Research 100 , 35-83).

TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, ETK2) was originally identified by PCR-based selection studies (Lai et al., Neuron 6 , 691-70, 1991; Graham et al., 2014, Nature Reviews Cancer 14 , 769-785; Linger et al., 2008, Advances in Cancer Research 100 , 35-83). Both ligands GAS6 and PROS1 can bind and activate TYRO3. Although the downstream signal transduction pathway of TYRO3 activation is the least studied among TAM RTKs, it seems to cover both PI3K-Akt and Raf-MAPK pathways (Linger et al., 2008, Advances in Cancer Research 100 , 35-83). AXL, MER and TYRO3 were found to be overexpressed in cancer cells.

Accordingly, there is a need for compounds and methods of use for modulating TAM kinases in cancer treatment.

In one aspect, the present application relates to compounds of formula I: or a pharmaceutically acceptable salt thereof, wherein the variables R ¹ , R ² , R ³ , Cy ^C and Cy ^B are as described herein.

The present application further provides compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

The present application also provides methods of inhibiting TAM kinases, and in one embodiment, provides methods of inhibiting AXL and MER kinases, comprising combining one or more TAM kinases with a compound described herein or a pharmaceutically acceptable salt thereof get in touch with.

This application also provides compounds described herein, or pharmaceutically acceptable salts thereof, for use in any of the methods described herein.

This application further provides the use of a compound described herein, or a pharmaceutically acceptable salt thereof, to manufacture a medicament for use in any of the methods described herein.

[ Cross-references to related applications ]

This application claims U.S. Provisional Patent Application No. 62/314,066 filed on March 28, 2016, U.S. Provisional Patent Application No. 62/362,934 filed on July 15, 2016, and U.S. Provisional Patent Application No. 62/362,934 filed on December 23, 2016. Priority is claimed from U.S. Provisional Patent Application No. 62/438,750; the entire text of which is incorporated herein by reference.

In particular, this application provides compounds of formula I: Or its pharmaceutically acceptable salt, wherein: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl group, C _1-4 alkoxy group, C _1-4 haloalkoxy group, cyano-C _1-3 alkyl group or C _1-6 alkoxyalkyl group; R ³ is H, halo group, CN, C _1-6 alkyl, C _1-6 haloalkyl, OR ^a , SR ^a , C(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c S(O) ₂ R ^b or S(O) ₂ R ^b ; wherein the C _1-6 alkyl group and C _1-6 haloalkyl group are independently selected from halo group, CN, OR ^a and SR ^a via 1, 2 or 3 as appropriate. , C(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c S(O) ₂ R ^b , S(O) ₂ R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O) ₂ NR ^c R ^d and Cy ^R3 are substituted by substituents; A ¹ is selected from one bond, Cy ^A1 , -Y-, -C _{1- 3} Alkylene-, -C _1-3 Alkylene-Y-, -YC _1-3 Alkylene- and -C _1-2 Alkylene-YC _1-2 Alkylene-; wherein these alkylene Each alkyl group is independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 Substitution of haloalkoxy, amine, C _1-3 alkylamino and di(C _1-3 alkyl)amine groups; A ² is selected from one bond, Cy ^A2 , -Y-, -C _{1 -3} Alkylene-, -C _1-3 Alkylene-Y-, -YC _1-3 Alkylene- and -C _1-2 Alkylene-YC _1-2 Alkylene-; wherein Each alkylene group is independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _{1- 3} haloalkoxy, amino, C _1-3 alkylamino and di(C _1-3 alkyl) amino substituents; A ³ is selected from one bond, Cy ^A3 , -Y-, -C _1-3 Alkylene-, -C _1-3 Alkylene-Y-, -YC _1-3 Alkylene- and -C _1-2 Alkylene-YC _1-2 Alkylene-; wherein Each isoalkylene group is independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _{1 -3} haloalkoxy, amino, C _1-3 alkylamino and di(C _1-3 alkyl)amine substituents; R ^A is H, C _1-6 alkyl, C _1-6 Haloalkyl, halo, C _3-6 cycloalkyl, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC (O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 OR ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S( O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; Y is O, S, S(O) , S(O) ₂ , C(O), C(O)NR ^f , NR ^f C(O), NR ^f C(O)NR ^f , NR ^f S(O) ₂ NR ^f , S(O) ₂ NR ^f , NR ^f S(O) ₂ or NR ^f ; Each R ^f is independently selected from H and C _1-3 alkyl; Cy ^A1 is C _3-7 cycloalkyl, phenyl, 5- to 6-membered hetero Aryl or 4- to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 independently selected Ring-forming heteroatoms from N, O and S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups To form a carbonyl group; and wherein each of C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl is independently selected from R by 1, 2, 3 or 4 as appropriate. The substituents of ^A1 are substituted; Each R ^A1 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1- 6} haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _1-6 alkylamino, di(C _{1- 6} alkyl) amino group, thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfonyl group, C _1-6 alkyl sulfonyl group, aminoformyl group, C _1-6 alkyl group Aminoformyl, bis(C _1-6 alkyl)aminoformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _{1- 6} alkylsulfonylamine group, aminosulfonylamine group, C _1-6 alkylaminosulfonylamine group, two (C _1-6 alkyl) aminosulfonylamine group, aminosulfonylamine group, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _{1 -6} alkyl) aminocarbonylamino; Cy ^A2 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; each of which is 5 to 6 membered hetero Aryl groups and 4- to 7-membered heterocycloalkyl groups have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized ; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with side oxygen groups to form carbonyl; and wherein C _3-7 cycloalkyl, phenyl, 5 to 6 Each of the membered heteroaryl and the 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A2 ; each R ^A2 is independently selected from OH, NO ₂ , CN _, halo, C _1-6 alkyl, C 1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _{1 -3} alkyl group, H ₂ NC _1-3 alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _1-6 alkylthio group, C _{1 -6} alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl) amine methyl group, carboxyl group , C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, amidosulfonyl, C _1-6 alkyl Aminosulfonyl, bis(C _1-6 alkyl)aminosulfonyl, amidosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl) )Aminosulfonylamine group, aminocarbonylamino group, C _1-6 alkylaminocarbonylamino group and di(C _1-6 alkyl)aminocarbonylamino group; Cy ^A3 is C _3-7 cycloalkyl base, phenyl, 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl have at least one ring-forming carbon atom and 1 , 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are The ring carbon atoms are optionally substituted with pendant oxygen groups to form carbonyl; and wherein C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2 , 3 or 4 substituted with substituents independently selected from ^RA3 ; Each R ^A3 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _{1- 6} alkylamino group, di(C _1-6 alkyl)amine group, sulfide group, C _1-6 alkylthio group, C _1-6 alkyl sulfonyl group, C _1-6 alkyl sulfonyl group, amine Formyl, C _1-6 alkylamineformyl, di(C _1-6 alkyl)amineformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _{1- 6} alkylcarbonylamino, C _1-6 alkylsulfonylamine, amidosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl , aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkyl Aminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^R3 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl group; wherein each 5- to 6-membered heteroaryl group and 4- to 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroaromatic groups independently selected from N, O and S. atoms; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxy groups to form carbonyl groups; and wherein C _3-7 Cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; Cy ^C is the extension Phenyl or 5- to 6-membered heteroaryl; wherein the 5- to 6-membered heteroaryl has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O and S; and wherein Each of the phenylene group and the 5- to 6-membered heteroaryl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently selected from OH, CN, halo, C _1-4 alkyl, C _1-3 haloalkyl, C _1-4 alkoxy, C _1-3 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl , Amino group, C _1-4 alkylamino group, di(C _1-4 alkyl) amino group, C _1-4 alkyl sulfenyl group, C _1-4 alkyl sulfonyl group, amine methacryl group, C _1-4 alkylamine methanoyl, di(C _1-4 alkyl) amine methanoyl, carboxyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkylcarbonyl Amino, C _1-4 alkylsulfonylamine, aminosulfonyl, C _1-4 alkylaminosulfonyl and di(C _1-4 alkyl)aminosulfonyl; Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; or Cy ^B is a 6 to 10 membered aryl group Or 5 to 10 membered heteroaryl; wherein the 5 to 10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S is optionally oxidized; wherein: (a) at least one ring-forming carbon atom of a 5- to 10-membered heteroaryl group is substituted with a pendant oxygen group to form a carbonyl group; or (b) a 6- to 10-membered aryl group or a 5- to 10-membered aryl group The heteroaryl group is modified by a halo group, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC( O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S( O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 substituted; and wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; Each R ^B is independently selected from halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered hetero Aryl, 4 to 7-membered heterocycloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O) R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^{c2 C} (O)NR ^c2 R ^d2 ,NR ^c2 S(O)R ^b2 ,NR ^c2 S(O) ₂ R ^b2 ,NR ^c2 S(O) ₂ NR ^c2 R ^d2 ,S(O)R ^b2 ,S(O)NR ^c2 R ^d2 ,S( O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein the C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ¹¹ is independently selected from CN, NO ₂ , OR ^a3 , SR ^a3 ,C(O)R ^b3 ,C(O)NR ^c3 R ^d3 ,C(O)OR ^a3 ,OC(O)R ^b3 ,OC(O)NR ^c3 R ^d3 ,NR ^c3 R ^d3 ,NR ^c3 OR ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ¹² independently Selected from halo, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycle Alkyl group, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 OR ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 C(O)NR ^c4 R ^d4 , NR ^c4 S(O)R ^b4 , NR ^c4 S( O) ₂ R ^b4 , NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups each undergo 1, 2, 3 or 4 as appropriate. Substituted with substituents independently selected from R ^g ; R ^a is selected from H, C _1-6 alkyl and C _1-6 haloalkyl; R ^b is selected from C _1-6 alkyl and C _1-6 halo Alkyl; R ^c and R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, 4 to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-3 alkylene, phenyl-C _1-3 alkylene, 5 to 6-membered heteroaryl-C _1-3 alkylene And 4 to 6 membered heterocycloalkyl-C _1-3 alkylene; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered Heteroaryl, 4- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-3 alkylene, phenyl-C _1-3 alkylene, 5- to 6-membered heteroaryl-C _{1 -3} alkylene and 4 to 6 membered heterocycloalkyl -C _1-3 alkylene are each optionally substituted with 1, 2 or 3 substituents independently selected from ^Rg ; R ^a1 , R ^c1 and R ^d1 is each independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 independently selected from R ^g or ^, alternatively, R ^c1 and R ^d1 connected to the same N atom together with the N atom to which they are connected form 4, 5, 4, 5, 6 or 7-membered heterocycloalkyl; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R ^g Substituted with a base; R ^e1 is selected from H, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkyl Carbonyl group, C _1-6 alkylamino sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl) amine methyl group, amine sulfonyl group, C _1-6 alkylaminosulfonyl and di(C _1-6 alkyl)aminosulfonyl; each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl group, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; or alternatively, connected to the same Any R ^c2 and R ^d2 of N atoms together with the N atom to which they are attached form a 4, 5, 6 or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² ; Each R ^b2 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Each R ^a3 , R ^c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene , phenyl-C _1-4 alkylene group, 5 to 6-membered heteroaryl-C _1-4 alkylene group and 4 to 7-membered heterocycloalkyl-C _1-4 alkylene group; wherein the C _{1- 6} alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl -C _1-4 alkylene group, 5- to 6-membered heteroaryl-C _1-4 alkylene group, and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene group are each optionally represented by 1, 2, or 3 Or substituted with 4 substituents independently selected from R ^g ; or alternatively, any R ^c3 and R ^d3 connected to the same N atom together with the N atom to which they are connected form a group consisting of 1, 2 or 3 independently selected substituents as the case may be. 4, 5, 6 or 7-membered heterocycloalkyl substituted by the substituent of R ^g ; each R ^b3 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl base, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6-membered heteroaryl-C _1-4 alkylene and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene, each of which is independently selected from R via 1, 2, 3 or 4 as appropriate. ^g is substituted with a substituent; each R ^a4 , R ^c4 and R ^d4 are independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally replaced by 1, Substituted with 2, 3 or 4 substituents independently selected from R ^g ; or alternatively, any R ^c4 and R ^d4 attached to the same N atom together with the N atom to which they are attached are optionally substituted by 1, 2 or 3 is independently selected from 4, 5, 6 or 7-membered heterocycloalkyl substituted by the substituent of R ^g ; each R ^b4 is independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is The case is substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; and each R ^g is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _{1- 6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, Amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 alkyl group Sulfonyl group, aminoformyl group, C _1-6 alkylamineformyl group, di(C _1-6 alkyl)aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkyl group Oxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, aminosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl )Aminosulfonylamine, C 1-6 alkylaminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino , C _1-6 alkylaminocarbonylamino group and di(C _1-6 alkyl)aminocarbonylamino group; The restrictions are: 1) When one of A ¹ , A ² or A ³ is a bond or YYY When, A ¹ -A ² -A ³ is not YY; and 2) When A ³ is -Y- or -C _1-3 alkyl-Y-, then R ^A is H, C _1-6 alkyl or C _1-6 haloalkyl, wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In some embodiments, provided herein are compounds of formula (I), or pharmaceutically acceptable salts thereof, wherein: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H, halo, CN _, C _1-4 alkyl, C _1-4 haloalkyl, C 1-4 alkoxy, C _1-4 haloalkoxy, cyano-C _1-3 alkyl or C _1-6 alkoxy Alkyl group; R ³ is H, halo group, CN, C _1-6 alkyl group, C _1-6 haloalkyl group, OR ^a , SR ^a , C(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c S(O) ₂ R ^b or S(O) ₂ R ^b ; wherein the C _1-6 alkyl and C _1-6 haloalkyl are passed through 1, 2 or 3 as appropriate are independently selected from halo, CN, OR ^a , SR ^a , C(O)NRc R ^d , NR ^c R ^d , NR ^c C(O)R ^b , ^{NR c S} (O) ₂ R ^b , S (O) ₂ R ^b , NR ^c C(O)OR ^a , NR ^c C(O)NR ^c R ^d , NR ^c S(O) ₂ NR ^c R ^d and Cy ^R3 substituent substitution; A ¹ is selected From one bond, Cy ^A1 , -Y-, -C _1-3 alkylene-, -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 alkylene Base -YC _1-2 alkylene-; wherein each of these alkylene groups is independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkyl by 1, 2 or 3 as appropriate. Substituent substitution of oxygen group, C _1-3 haloalkyl group, C _1-3 haloalkoxy group, amino group, C _1-3 alkylamino group and di(C _1-3 alkyl)amine group; A ² series Selected from one bond, Cy ^A2 , -Y-, -C _1-3 alkylene-, -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 alkylene Alkyl-YC _1-2 alkylene-; wherein each of the alkylene groups is independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 by 1, 2 or 3 as appropriate Substituents of alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, amine, C _1-3 alkylamino and di(C _1-3 alkyl)amine; A ³ The system is selected from one bond, Cy ^A3 , -Y-, -C _1-3 alkylene-, -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 Alkylene-YC _1-2 Alkylene-; wherein each of the alkylene groups is independently selected from halo, CN, OH, C _1-3 alkyl, C _{1- 3} alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, amino, C _1-3 alkylamino and di(C _1-3 alkyl)amino substituents; R ^A is H, C _1-6 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C (O)OR ^a1 , OC(O)R ^b1 , OC(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , NR ^c1 OR ^d1 , NR ^c1 C(O)R ^b1 , NR ^c1 C(O)OR ^a1 , NR ^c1 C(O)NR ^c1 R ^d1 , C(=NR ^e1 )R ^b1 , C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O) R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S (O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; Y is O , S, S(O), S(O) ₂ , C(O), C(O)NR ^f , NR ^f C(O), NR ^f C(O)NR ^f , NR ^f S(O) ₂ NR ^f , S(O) ₂ NR ^f , NR ^f S(O) ₂ or NR ^f ; Each R ^f is independently selected from H and C _1-3 alkyl; Cy ^A1 is C _3-7 cycloalkyl, benzene base, 5- to 6-membered heteroaryl group or 4- to 7-membered heterocycloalkyl group; wherein each 5- to 6-membered heteroaryl group and 4- to 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl ring carbon atoms Optionally substituted with a pendant oxygen group to form a carbonyl group; and wherein C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or Substituted with 4 substituents independently selected from R ^A1 ; each R ^A1 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 Alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _1-6 alkylamine Base, di(C _1-6 alkyl)amine group, sulfo group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group , C _1-6 alkylamine methane group, di(C _1-6 alkyl) amine methane group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkyl group Carbonylamine group, C _1-6 alkylsulfonylamine group, aminosulfonyl group, C _1-6 alkylaminosulfonyl group, di(C _1-6 alkyl)amidosulfonyl group, amino group Sulfonylamine group, C _1-6 alkylaminosulfonylamine group, di(C _1-6 alkyl)aminosulfonylamine group, aminocarbonylamino group, C _1-6 alkylaminocarbonyl group Amino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^A2 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; wherein Each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxy groups to form carbonyl groups; and wherein C _3-7 cycloalkyl , phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A2 ; each R ^A2 is independently selected From OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 Alkyl group, HO-C _1-3 alkyl group, H ₂ NC _1-3 alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _{1- 6} alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl group )Aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylsulfonylamine group, aminosulfonyl group base, C _1-6 alkylaminosulfonylamine group, di(C _1-6 alkyl)aminosulfonylamine group, C 1-6 alkylaminosulfonylamine group, di(C _1-6 alkyl)aminosulfonylamine group (C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^A3 is C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl or 4- to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl has at least One ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein C _3-7 cycloalkyl and 4 to 7 The ring carbon atoms of the heterocycloalkyl group are optionally substituted with pendant oxygen groups to form carbonyl groups; and among them, C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl Each is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A3 ; each R ^A3 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl , Amino group, C _1-6 alkylamino group, di(C _1-6 alkyl) amino group, thio group, C _1-6 alkylthio group, C _1-6 alkylsulfenyl group, C _1-6 Alkyl sulfonyl, aminoformyl, C _1-6 alkylamineformyl, di(C _1-6 alkyl)amineformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 Alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, amidosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl base) aminosulfonylamine, aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamine base, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^R3 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; wherein each 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl have at least one ring carbon atom and 1, 2, 3 or 4 independently selected from N, The ring-forming heteroatoms of O and S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxy groups to form carbonyl groups ; And wherein C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted by 1, 2, 3 or 4 independently selected from R ^g Substituted with a base; Cy ^C is a phenylene group or a 5- to 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group has at least one ring carbon atom and 1 or 2 independently selected from N, O and S Ring-forming heteroatoms; and wherein the phenylene group and the 5- to 6-membered heteroaryl group are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently selected from OH, CN, halo, C _1-4 alkyl, C _1-3 haloalkyl, C _1-4 alkoxy, C _1-3 haloalkoxy, cyano-C _1-3 alkyl, HO -C _1-3 alkyl, amino, C _1-4 alkylamino, di(C _1-4 alkyl)amine, C _1-4 alkyl sulfenyl, C _1-4 alkyl sulfonyl base, aminoformyl group, C _1-4 alkylamineformyl group, di(C _1-4 alkyl)amineformyl group, carboxyl group, C _1-4 alkylcarbonyl group, C _1-4 alkoxycarbonyl group, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamine, aminosulfonyl, C _1-4 alkylaminosulfonyl and di(C _1-4 alkyl)amine Sulfonyl group; Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl has a pendant The oxygen group is substituted to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S is optionally oxidized; and wherein C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; or Cy ^B It is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group has at least one ring carbon atom and 1, 2, 3 or 4 independently selected from N, O and S Ring-forming heteroatoms; wherein N and S are optionally oxidized; wherein: (a) at least one ring-forming carbon atom of a 5- to 10-membered heteroaryl is substituted with a pendant oxygen group to form a carbonyl group; or (b) a 6- to 10-membered heteroaryl group Aryl or 5 to 10-membered heteroaryl through halo group, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC( O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R d2 , S(O) ^{R b2 ,} S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 are substituted; and wherein 6 to 10 membered aryl or 5 to 10 membered heteroaryl is optionally selected from 1, 2, 3 or 4 independently The substituents of R ^B are further substituted; each R ^B is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered hetero Aryl, 4 to 7-membered heterocycloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O) R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^{c2 C} (O)NR ^c2 R ^d2 ,NR ^c2 S(O)R ^b2 ,NR ^c2 S(O) ₂ R ^b2 ,NR ^c2 S(O) ₂ NR ^c2 R ^d2 ,S(O)R ^b2 ,S(O)NR ^c2 R ^d2 ,S( O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycle Each alkyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ¹¹ is independently selected from CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 OR ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 OR ^d4 ,NR ^c4 C(O)R ^b4 ,NR ^c4 C(O)OR ^a4 ,NR ^c4 C(O)NR ^c4 R ^d4 ,NR ^c4 S(O)R ^b4 ,NR ^c4 S(O) ₂ R ^b4 ,NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C _{1- 6} alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl are each independently selected from ^Rg by 1, 2, 3 or 4 as appropriate. Substituent substitution; R ^a is selected from H, C _1-6 alkyl and C _1-6 haloalkyl; R ^b is selected from C _1-6 alkyl and C _1-6 haloalkyl; R ^c and R ^d is each independently selected from H, C _1-6 alkyl, C 1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, _5- to 6-membered heteroaryl, 4- to 6-membered heterocycloalkyl , C _3-6 cycloalkyl-C _1-3 alkylene group, phenyl-C _1-3 alkylene group, 5 to 6 membered heteroaryl-C _1-3 alkylene group and 4 to 6 membered heterocycle Alkyl-C _1-3 alkylene; wherein the C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 6 Member heterocycloalkyl, C _3-6 cycloalkyl-C _1-3 alkylene, phenyl-C _1-3 alkylene, 5 to 6-membered heteroaryl-C _1-3 alkylene and 4 Each of the 6-membered heterocycloalkyl-C _1-3 alkylene groups is optionally substituted with 1, 2 or 3 substituents independently selected from ^Rg ; R ^a1 , R ^c1 and R ^d1 are each independently selected from H , C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from ^Rg ; or alternatively, connected R ^c1 and R ^d1 to the same N atom together with the N atom to which they are attached form a 4, 5, 6 or 7-membered heterocycloalkane optionally substituted with 1, 2 or 3 substituents independently selected from R ^g group; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ^g ; R ^e1 is selected from From H, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 alkylcarbonyl, C _1-6 Alkylaminosulfonyl, aminoformyl, C _1-6 alkylamineformyl, di(C _1-6 alkyl)amineformyl, aminosulfonyl, C _1-6 alkylamino Sulfonyl and di(C _1-6 alkyl) aminosulfonyl groups; Each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5 to 7 Each of the 6-membered heteroaryl and the 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; or alternatively, any R ^c2 and attached to the same N atom R ^d2 together with the N atom to which it is attached forms a 4, 5, 6 or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² ; each R ^b2 is independently Selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl, each of which is optionally processed 1, 2, 3 or 4 substituted substituents independently selected from R ¹² ; Each R ^a3 , R ^c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl -C _{1- 4-} alkyl alkylene, 5- to 6-membered heteroaryl-C _1-4 alkylene and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene; wherein the C _1-6 alkyl, C _{3- 6-} cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene group, 5- to 6-membered heteroaryl-C _1-4 alkylene group and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene group are each independently selected from 1, 2, 3 or 4 as appropriate. Substituted with a substituent for R ^g ; or alternatively, any R ^c3 and R ^d3 attached to the same N atom, together with the N atom to which they are attached, are optionally substituted with 1, 2 or 3 substituents independently selected from R ^g 4, 5, 6 or 7-membered heterocycloalkyl; each R ^b3 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5- to 6-membered heteroaryl- C _1-4 alkylene and 4 to 7 membered heterocycloalkyl-C _1-4 alkylene, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; each Each R ^a4 , R ^c4 and R ^d4 are independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally separated by 1, 2, 3 or 4 independently is substituted with a substituent independently selected from R ^g ; or alternatively, any R ^c4 and R ^d4 connected to the same N atom, together with the N atom to which they are connected, form optionally by 1, 2 or 3 independently selected from R ^g 4, 5, 6 or 7-membered heterocycloalkyl substituted by substituents; each R ^b4 is independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally modified by 1, 2, 3 Or substituted by 4 substituents independently selected from R ^g ; and each R ^g is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _{1 -6} alkoxy, C _1-6 haloalkoxy, cyano -C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _1-6 Alkylamino, di(C _1-6 alkyl)amine, sulfide, C _1-6 alkylthio, C _1-6 alkylsulfenyl, C _1-6 alkylsulfonyl, amine methyl Carboxyl group, C _1-6 alkylamine methane group, di(C _1-6 alkyl) amine methane group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 Alkylcarbonylamino, C _1-6 alkylsulfonylamine, amidosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl, Aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylamine Carbonylamine group and di(C _1-6 alkyl)aminocarbonylamine group; The restrictions are: 1) When one of A ¹ , A ² or A ³ is a bond or YYY, A ¹ -A ² -A ³ is not YY; and 2) When A ³ is -Y- or -C _1-3 alkylene-Y-, then R ^A is H, C _1-6 alkyl or C _1-6 haloalkyl , wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In some embodiments, A ¹ is a key.

In some embodiments, ^A2 is a key.

In some embodiments, ^A3 is a key.

In some embodiments, R ^A is H, halo, C _1-6 alkyl, or C _1-6 haloalkyl.

In some embodiments, ^RA is C _1-6 alkyl.

In some embodiments, R ^A is methyl or ethyl.

In some embodiments, A ¹ is a key. For example, R ¹ is A ² -A ^{3 -RA} .

In some embodiments, A ¹ is a bond, A ² is a bond, and A ³ is Cy ^A3 . For example, R ¹ is Cy ^{A3 -RA} .

In some embodiments, one of A ¹ , A ² and A ³ is not a key.

In some embodiments, one of A ¹ , A ² and A ³ is -C _1-3 alkylene-, -Y-, -C _1-3 alkylene-Y- or -YC _1-3 alkylene base-. In some embodiments, one of A ¹ , A ² and A ³ is -C _1-6 alkylene- or -Y-. In some embodiments, one of A ¹ , A ² and A ³ is -C _1-6 alkylene-. In some embodiments, one of A ¹ , A ² and A ³ is methylene.

In some embodiments, R ¹ is H, halo, C _1-6 alkyl, or C _1-6 haloalkyl.

In some embodiments, R ¹ is C _1-6 alkyl. In some embodiments, ^R1 is methyl or ethyl.

In some embodiments, R ¹ is A ² -A ^{3 -RA} .

In some embodiments, R ¹ is Cy ^{A3 -RA} .

In some embodiments, Cy ^A3 is C _3-7 cycloalkyl, 5- to 6-membered heteroaryl, or 4- to 7-membered heterocycloalkyl; each is independently selected from 1, 2, 3, or 4 as appropriate. R ^A3 substituent substitution.

In some embodiments, Cy ^A3 is C _3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1 or 2 substituents independently selected from ^RA3 .

In some embodiments, Cy ^A3 is piperidinyl, cyclohexyl or tetrahydropyranyl; each is optionally substituted with 1 or 2 substituents independently selected from R ^A3 .

In some embodiments, Cy ^A3 is C _3-6 cycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected ^RA3 groups. In some embodiments, Cy ^A3 is cyclohexyl and cyclopropyl, optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is a 4- to 6-membered heterocycloalkyl optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups. In some embodiments, Cy ^A3 is piperidinyl or morpholinyl, optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is a 5- to 10-membered heteroaryl group optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups. In some embodiments, Cy ^A3 is pyridinyl, optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is piperidinyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, pyridyl, azetidinyl, cyclopropyl, or morpholinyl; each optionally modified by 1 or Substituted with 2 substituents independently selected from R ^A3 .

In some embodiments, Cy ^A3 is piperidinyl, pyridyl, morpholinyl, cyclohexyl, or tetrahydropyranyl; each is optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is piperidinyl, optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is cyclohexyl optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is morpholinyl optionally substituted with 1, 2, 3, or 4 independently selected R ^A3 groups.

In some embodiments, Cy ^A3 is , or , Cy ^{A3-1 CyA3-2 CyA3-3} Each of Cy ^A3 -1, Cy ^A3 -2 and Cy ^A3 -3 is optionally substituted with 1, 2 or 3 substituents independently selected from R ^A3 .

In some embodiments, A ¹ is a bond, A ² is a bond, A ³ is a bond and R ^A is methyl or ethyl; or A ¹ is a bond, A ² is a bond and A ³ is optional. From Cy ^A3 -R ^A , and .

In some embodiments, ^RA is C _1-6 alkyl, CN, OR ^a1 , NR ^c1 R ^d1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , S (O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl group is optionally separated by 1 or 2 independently Substitution with a substituent selected from R ¹¹ is subject to the proviso that if ^RA is attached to a nitrogen atom, ^RA is not CN, OR ^a1 or NR ^c1 R ^d1 .

In some embodiments, ^RA is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 and S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted with 1 substituent selected from R ¹¹ , with the restriction that if ^RA is connected to a nitrogen atom, ^RA is not CN or OR ^a1 . In some embodiments, R ^b1 is isopropyl.

In some embodiments, each R ^A is independently selected from C _1-3 alkyl, CN, OH, methylcarbonyl, methoxycarbonyl, N,N-dimethylaminocarbonyl, and methylsulfonyl, wherein The C _1-3 alkyl group is optionally substituted with an OH or OCH ₃ group, with the proviso that if ^RA is attached to a nitrogen atom, then ^RA is not CN or OH.

In some embodiments, each ^RA is independently _selected from _CH3 , _CH2CH3 , CN _, OH, _CH2CH2OH , _{CH2CH2OCH3 ,} C(O) _CH3 , C( _O ) CH ₂ OH, C(O)CH(OH)CH ₃ , S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NHCH ₃ , C( O)N(CH ₂ CH ₃ ) ₂ and C(O)N(CH ₃ )(CH ₂ CH ₃ ).

In some embodiments, each ^RA is independently _selected from _CH3 , _CH2CH3 , CH( _CH3 ) ₂ , _CN , OH, _{CH2CH2OH , CH2CH2OCH3 ,} C(O) CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH ₃ ) ₂ , C(O)CH ₂ OH, C(O)CH(OH)CH ₃ , S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)N(CH ₂ CH ₃ ) ₂ , C(O)N(CH ₃ )(CH ₂ CH ₃ ), C(O )NHCH ₃ , C(O)NH(CH ₂ CH ₃ ) and C(O)[morpholin-4-yl].

In some embodiments, each R ¹¹ is independently OR ^a3 .

In some embodiments, each R ¹¹ is independently OH or OCH ₃ .

In some embodiments, Cy ^A3 is piperidinyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, pyridyl, azetidinyl, cyclopropyl, or morpholinyl; each, as appropriate, independently Selected from CH ₃ , CN, OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH ₃ ) ₂ , C (O)CH ₂ OH, C(O)CH(CH ₃ )OH, S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NH( CH ₃ ), C(O)N(CH ₂ CH ₃ ) ₂ , C(O)NH(CH ₂ CH ₃ ), C(O)N(CH ₃ )(CH ₂ CH ₃ ), CH ₂ C(O )N(CH ₃ ) ₂ , 1-methyl-2-side-oxypyrrolidin-3-yl, C(O)(cyclopropyl), N(CH ₃ ) ₂ and C(O)(morpholine- 4-yl) substituted by R ^A.

In some embodiments, Cy ^A3 is piperidinyl, cyclohexyl, or tetrahydropyranyl; each is independently selected from _CH3 , CN, OH _{, CH2CH2OH , CH2CH2OCH3 ,} C(O)CH ₃ , C(O)CH ₂ OH, C(O)CH(CH ₃ )OH, S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) _2. C(O)NH(CH ₃ ), C(O)N(CH ₂ CH ₃ ) ₂ , C(O)NH(CH ₂ CH ₃ ) and C(O)N(CH ₃ )(CH ₂ CH ₃ ) replaced by R ^A.

In some embodiments, Cy ^A3 is piperidinyl, cyclohexyl, or tetrahydropyranyl; each is independently selected from CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CN, OH, CH as appropriate ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH ₂ CH ₃ , C(O)CH(CH ₃ ) ₂ , C(O)CH ₂ OH, C(O )CH(OH)CH ₃ , S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)N(CH ₂ CH ₃ ) ₂ , C(O ^RA substitution of )N(CH ₃ )(CH ₂ CH ₃ ), C(O)NHCH ₃ , C(O)NH(CH ₂ CH ₃ ) and C(O)(morpholin-4-yl).

In some embodiments, Cy ^A3 is piperidinyl, pyridyl, morpholinyl, cyclohexyl or tetrahydropyranyl; each is independently selected from CH ₃ , CH ₂ via 1, 2, 3 or 4 as appropriate. CH ₃ , CN, OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH ₂ OH, C(O)CH(OH)CH ₃ , S(O) ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NHCH ₃ , C(O)N(CH ₂ CH ₃ ) ₂ and C(O)N(CH ₃ )(CH ₂ CH ₃ ) group substitution.

In some embodiments, A ¹ is a bond, A ² is Cy ^A2 , A ³ is -Y-, R ^A is C _3-6 cycloalkyl (e.g., cyclopropyl), and -Y- is C(O ) and Cy ^A2 is 4- to 7-membered heterocycloalkyl (eg, piperidinyl).

In some embodiments, ^R1 is . In some embodiments, ^R1 is . In some embodiments, ^R1 is . In some embodiments, ^R1 is . In some embodiments, ^R1 is .

In some embodiments, ^R2 is H, halo, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy, or C _1-4 haloalkoxy. In some embodiments, ^R2 is H or C _1-4 alkyl. In some embodiments, ^R2 is H.

In some embodiments, ^R3 is H.

In a preferred embodiment, Cy ^B forms a hydrogen bond with the NH of the amide group. For example, if the Cy ^B group has a pendant oxygen group, Cy ^B can form a hydrogen bond through the NH of the carbonyl group and the amide group. Similarly, Cy ^B may be substituted with an electron-donating substituent capable of forming a hydrogen bond with the NH of the amide group. The following are illustrative examples, where W is an electron-donating group, such as halo, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR c2 C(O)R ^b2 , NR ^{c2 C} (O)OR ^a2 , NR ^c2 C( O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R d2 , S( ^{O)R b2 ,} S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 .

In some embodiments, Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl Substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein each of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; or Cy ^B is a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- to 10-membered heteroaryl group is substituted with a pendant oxygen group to form a carbonyl group; or (b) the 5- to 10-membered heteroaryl group is halogenated Base, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 substituted; and wherein the 5 to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from ^RB .

In some embodiments, Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl Substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein each of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^RB .

In some embodiments, Cy ^B is a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 independently selected from N, O, and S of ring-forming heteroatoms; wherein N and S are optionally oxidized; wherein: (a) at least one ring-forming carbon atom of the 5- to 10-membered heteroaryl is substituted with a pendant oxygen group to form a carbonyl group; or (b) 5 to 10 Member heteroaryl group via halo group, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC (O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S (O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 are substituted; and the 5 to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B.

In some embodiments, Cy ^B is a 4- to 10-membered heterocycloalkyl; wherein at least one ring carbon atom of the 4- to 10-membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycle The alkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and wherein the 4 to 10-membered heterocycloalkyl group is optionally modified by 1, 2 or 4 ring-forming heteroatoms. Substituted with 3 substituents independently selected from R ^B ; or Cy ^B is a 5- to 6-membered heteroaryl group, which has at least one ring-forming carbon atom substituted with a pendant oxygen group to form a carbonyl group and has 1 or 2 independently selected Ring-forming heteroatoms from N, O and S; wherein N and S are optionally oxidized; wherein the 5- to 6-membered heteroaryl group is optionally further substituted with 1, 2 or 3 substituents independently selected from ^RB .

In some embodiments, Cy ^B is a 4- to 10-membered heterocycloalkyl; wherein at least one ring carbon atom of the 4- to 10-membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycle The alkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and wherein the 4 to 10-membered heterocycloalkyl group is optionally modified by 1, 2 or 4 ring-forming heteroatoms. Substituted with 3 substituents independently selected from R ^B.

In some embodiments, Cy ^B is a 5- to 10-membered heteroaryl group having at least one ring-forming carbon atom substituted with a pendant oxygen group to form a carbonyl group and having 1 or 2 members independently selected from N, O, and S. Ring heteroatoms; wherein N and S are optionally oxidized; wherein the 5- to 6-membered heteroaryl group is optionally further substituted with 1, 2 or 3 substituents independently selected from R ^B.

In some embodiments, Cy ^B is a 4- to 10-membered heterocycloalkyl group or a 5- to 10-membered heteroaryl group, in which one of the ring-forming carbon atoms in the ortho position is substituted with a pendant oxygen group to form a carbonyl group. Ortho position refers to the ring-forming carbon atom directly adjacent to the ring-forming atom connecting the Cy ^B group to the -C(=O)NH-Cy ^C -linker.

In some embodiments, Cy ^B is , , , , , ^CyB -1 ^CyB -2 ^CyB -3 ^CyB -4 ^CyB -5 or ^CyB -6 ^CyB -7 Among them, Cy ^B -1, Cy ^B -2, Cy ^B -3, Cy ^B -4, Cy ^B -5, Cy ^B -6 and Cy ^B -7 each undergo 1, 2 or 3 independently selected R ^B as the case may be. group substitution.

In some embodiments, Cy ^B is , , or ^CyB -8 ^CyB -9 ^CyB -10 ^CyB -11 Each of Cy ^B -8, Cy ^B -9, Cy ^B -10, Cy ^B -4 and Cy ^B -11 is substituted with 1, 2 or 3 independently selected ^RB groups as appropriate.

In some embodiments, Cy ^B is , , , ^CyB -1 ^CyB -2 ^CyB -3 , , or ^CyB -8 ^CyB -9 ^CyB -10 ^CyB -11 Among them, Cy ^B -1, Cy ^B -2, Cy ^B -3, Cy ^B -8, Cy ^B -9, Cy ^B -10, Cy ^B -4 and Cy ^B -11 each undergo 1, 2 or 3 as appropriate. Independently selected R ^B group substitutions.

In some embodiments, Cy ^B is Cy ^B -1 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -2 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -3 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -4 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -5 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -6 optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is Cy ^B -7 optionally substituted with 1, 2, or 3 independently selected ^RB groups.

In some embodiments, Cy ^B is , , , , , ^CyB -1a ^CyB -2a ^CyB -3a ^CyB -4a ^CyB -5a or ^CyB -6a ^CyB -7a.

In some embodiments, Cy ^B is Cy ^B -1a. In some embodiments, Cy ^B is Cy ^B -2a. In some embodiments, Cy ^B is Cy ^B -3a. In some embodiments, Cy ^B is Cy ^B -4a. In some embodiments, Cy ^B is Cy ^B -5a. In some embodiments, Cy ^B is Cy ^B -6a. In some embodiments, Cy ^B is Cy ^B -7a.

In some embodiments, Cy ^B is C _3-10 cycloalkyl optionally substituted with 1, 2, or 3 independently selected ^RB groups. In some embodiments, Cy ^B is cyclopropyl.

In some embodiments, Cy ^B is cyclopropyl, or , ^CyB -1 ^CyB -2 Wherein, cyclopropyl, Cy ^B -1 and Cy ^B -2 are each substituted with 1, 2 or 3 independently selected ^RB groups as appropriate.

In some embodiments, Cy ^B is , , or Cy ^B -1 Cy ^B -2 Cy ^B -3 Cy ^B -10 wherein Cy ^B -1, Cy ^B -2, Cy ^B -3 and Cy ^B -10 are each independently selected from 1, 2 or 3 as appropriate. Substituted by R ^B substituent.

In some embodiments, Cy ^B is or , ^CyB -1 ^CyB -2 Each of Cy ^B -1 and Cy ^B -2 is optionally substituted with 1, 2 or 3 independently selected ^RB groups.

In some embodiments, Cy ^B is , , , or , ^CyB -1 ^CyB -2 ^CyB -3 ^CyB -4 ^CyB -5 Each of Cy ^B -1, Cy ^B -2, Cy ^B -3, Cy ^B -4 and Cy ^B -5 is substituted with 1, 2 or 3 independently selected ^RB groups as appropriate.

In some embodiments, Cy ^B is or , ^CyB -1 ^CyB -2 Each of Cy ^B -1 and Cy ^B -2 is optionally substituted with 1, 2 or 3 substituents independently selected from ^RB .

In some embodiments, Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Each of Cy ^B -1, Cy ^B -2 and Cy ^B -3 is substituted by 1, 2 or 3 independently selected ^RB groups as appropriate.

In some embodiments, Cy ^B is , ^CyB -1 Where Cy ^B -1 is optionally substituted with 1, 2 or 3 independently selected ^RB groups.

In some embodiments, Cy ^B is , ^CyB -2 Where Cy ^B -2 is optionally substituted with 1, 2 or 3 independently selected ^RB groups.

In some embodiments, Cy ^B is , ^CyB -3 wherein Cy ^B -3 is optionally substituted with 1, 2 or 3 independently selected ^RB groups.

In some embodiments, Cy ^B is or , ^CyB -1 ^CyB -2 Wherein Cy ^B -1 and Cy ^B -2 are each optionally substituted with 1, 2 or 3 substituents independently selected from R ^B ; each R ^B is independently methyl, ethyl, isopropyl, the second Butyl or phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R ¹² ; each R ¹² is independently selected from halo, phenyl and OR ^a4 ; wherein the phenyl is optionally substituted with Substituted with 1 or 2 substituents independently selected from the R ^g group; each R ^a4 is H or C _1-3 alkyl; and each R ^g is independently selected from the halo group.

In some embodiments, Cy ^B is , , or , ^CyB -1 ^CyB -2 ^CyB -3 ^CyB -10 Wherein Cy ^B -1, Cy ^B -2, Cy ^B -3 and Cy ^B -10 are each optionally substituted with 1, 2 or 3 substituents independently selected from R ^B ; each R ^B is independently methyl , ethyl, isopropyl, 2-butyl, 2-pyridyl or phenyl, each of which is optionally substituted with 1 or 2 substituents independently selected from R ¹² ; each R ¹² is independently selected from C _1-6 alkyl, halo, phenyl and OR ^a4 ; wherein the C _1-6 alkyl and phenyl are each optionally substituted with 1 or 2 substituents independently selected from the R ^g group; each R ^a4 is H or C _1-3 alkyl; and each ^Rg is independently selected from halo.

In some embodiments, Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Wherein Cy ^B -1, Cy ^B -2 and Cy ^B -3 are each substituted with 1, 2 or 3 substituents independently selected from R ^B as appropriate; each R ^B is independently methyl, ethyl, iso Propyl, second butyl or phenyl, each optionally substituted with 1 or 2 substituents independently selected from R ¹² ; Each R ¹² is independently selected from halo, phenyl and OR ^a4 ; wherein the Phenyl is optionally substituted with 1 or 2 substituents independently selected from the R ^g group; each R ^a4 is H or C _1-3 alkyl; and each R ^g is independently selected from the halo group.

In some embodiments, Cy ^B is or , ^CyB -1 ^CyB -2 Wherein Cy ^B -1 and Cy ^B -2 are each independently selected from unsubstituted phenyl, 4-fluoro-phenyl, CH ₂ (phenyl), CH (CH ₂ OH ) phenyl, CH ₃ , CH ₂ CH ₃ , CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, OCH ₂ CH ₃ and OCH ₃ group substitutions.

In some embodiments, Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Wherein Cy ^B -1, Cy ^B -2 and Cy ^B -3 are each independently selected from the group consisting of unsubstituted phenyl, 4-fluoro-phenyl, 3-fluorophenyl, 2 -Fluorophenyl, 2-pyridyl, CH ₂ (phenyl), CH(CH ₂ OH)phenyl, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₂ OH)CH ₂ CH _3. Group substitution of CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, OCH ₂ CH ₃ and OCH ₃ .

In some embodiments, Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Wherein Cy ^B -1, Cy ^B -2 and Cy ^B -3 are each independently selected from unsubstituted phenyl, 4-fluoro-phenyl, 3-fluoro-phenyl, 1, 2 or 3 as appropriate. 2-Fluoro-phenyl, CH ₂ (phenyl), CH(CH ₂ OH)phenyl, CH ₃ , CH ₂ CH 3 , CH(CH ₃ ) ₂ , CH( _{CH 2 OH} )CH ₂ CH ₃ , CH (CH ₂ OH) CH ₃ , CH ₂ CH ₂ OH, OCH ₂ CH ₃ and OCH ₃ substituents are substituted.

In some embodiments, Cy ^B is or Cy ^B -2 Cy ^B -3, wherein Cy ^B -2 and Cy ^B -3 are each independently selected from unsubstituted phenyl, CH(CH ₃ ) ₂ and 2-pyridine by 1, 2 or 3 as appropriate. Substitution of base groups.

In some embodiments, Cy ^B is Cy ^B -2 wherein Cy ^B -2 is optionally substituted with 1, 2 or 3 groups independently selected from unsubstituted phenyl, CH(CH ₃ ) ₂ and 2-pyridyl.

In some embodiments, Cy ^B is Cy ^B -3, wherein Cy ^B -3 is optionally substituted with 1, 2 or 3 groups independently selected from unsubstituted phenyl, CH( _CH3 ) ₂ and 2-pyridyl.

In some embodiments, Cy ^B is Cy ^B -3, wherein Cy ^B -3 is substituted with unsubstituted phenyl and CH(CH ₃ ) ₂ .

In some embodiments, Cy ^B is Cy ^B -3, wherein Cy ^B -3 is substituted with pyridyl (eg, 2-pyridyl, 3-pyridyl, and 4-pyridyl) and CH( _CH3 ) ₂ .

In some embodiments, each R ^B is independently selected from halo, C _1-6 alkyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, CN, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 and NR ^c2 C(O)OR ^a2 ; wherein the C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered hetero Each of the aryl and 4- to 7-membered heterocycloalkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R12 .

In some embodiments, each R ^B is independently unsubstituted phenyl, 4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, CH ₂ (phenyl), CH(CH ₂ OH)phenyl, Br, Cl, CN, CH ₃ , CHF ₂ , CH 2 CH ₃ , CH ₂ OCH ₃ , CH _{2 OCH 2} CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₂ OH)CH ₂ CH _3. CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, CH ₂ CH(OH)(CH ₃ ), OCH ₃ , OCH ₂ CH ₃ , C(O)NH ₂ , C(O)CH ₃ , 2,5-Difluorophenyl, 3-pyridyl, 2 -pyridyl, 1-methyl-1H-pyrazol-4-yl, 1-methyl-1H - pyrazol-3-yl, 1 -Methyl- 1H -pyrazol-5-yl, 1,4-dimethyl- 1H -pyrazol-3-yl, 1,5-dimethyl- 1H -pyrazol-3-yl, 2-methylthiazol-5-yl, cyclohexyl, 3-cyanophenyl, 5-methylisoxazol-3-yl, 5-fluoropyridin-3-yl, 5-fluoropyridin-2-yl, 3-cyanophenyl, CH ₂ CN, thiazol-4-yl, 6-methylpyridin-3-yl, 2-methylpyridin-3-yl, 6-methylpyridin-2-yl, pyrimidine-2 -yl, morpholin-4-yl, cyclopropyl, oxazol-2-yl, CCCH(OH)(CH ₃ ) or C(O)NH (4-fluoro-phenyl).

In some embodiments, each R ^B is independently unsubstituted phenyl, 4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, CH ₂ (phenyl), CH(CH ₂ OH)phenyl, Br, CN, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, CH ₂ CH(OH)(CH ₃ ), OCH ₃ , OCH ₂ CH ₃ , C(O)NH ₂ , C(O)CH ₃ , 2,5-difluorophenyl, 3-pyridyl, 2-pyridine base, 1-methyl- 1H -pyrazol-4-yl, 1-methyl- 1H -pyrazol-3-yl, 1-methyl-1H - pyrazol-5-yl, 2-methyl Thiazol-5-yl, cyclohexyl, 3-cyanophenyl, 5-methylisoxazol-3-yl, 5-fluoropyridin-3-yl, 3-cyanophenyl, CH ₂ CN, thiazole -4-yl, 6-methylpyridin-3-yl, pyrimidin-2-yl, morpholin-4-yl, cyclopropyl, oxazol-2-yl, CCCH(OH)(CH ₃ ) or C( O)NH (4-fluoro-phenyl).

In some embodiments, each R ^B is independently unsubstituted phenyl, 4-fluoro-phenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridyl, CH ₂ (phenyl) , CH(CH ₂ OH)phenyl, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH , OCH ₃ , OCH ₂ CH ₃ or C(O)NH (4-fluoro-phenyl).

In some embodiments, each R ^B is independently unsubstituted phenyl, 4-fluoro-phenyl, CH ₂ (phenyl), CH(CH ₂ OH)phenyl, CH ₃ , CH ₂ CH ₃ , CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, OCH ₃ , OCH ₂ CH ₃ or C(O)NH (4-fluoro-phenyl).

In some embodiments, each R ^B is independently unsubstituted phenyl, 4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, CH ₂ (phenyl), CH ( CH ₂ OH)phenyl, CH ₃ , CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH, OCH ₃ , OCH ₂ CH ₃ or C(O)NH (4-fluoro-phenyl).

In some embodiments, each R ^B is independently unsubstituted phenyl or 4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, 2-pyridyl, CH ₃ , CH ₂ CH ₃ or CH(CH ₃ ) ₂ . In some embodiments, each R ^B is independently unsubstituted phenyl or 4-fluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, CH ₃ , CH ₂ CH ₃ or CH (CH ₃ ) ₂ . In some embodiments, each R ^B is unsubstituted phenyl, CH(CH ₃ ) ₂ , or 2-pyridyl. In some embodiments, each R ^B is independently unsubstituted phenyl or 4-fluoro-phenyl. In some embodiments, each R ^B is unsubstituted phenyl. In some embodiments, each R ^B is 4-fluoro-phenyl. In some embodiments, each R ^B is pyridyl (eg, 2-pyridyl). In some embodiments, each R ^B is independently unsubstituted phenyl or CH(CH ₃ ) ₂ . In some embodiments, each R ^B is independently unsubstituted phenyl or CH ₂ CH ₃ . In some embodiments, each R ^B is independently 4-fluoro-phenyl or CH(CH ₃ ) ₂ . In some embodiments, each R ^B is independently 4-fluoro-phenyl or CH ₂ CH ₃ . In some embodiments, each R ^B is independently 3-fluoro-phenyl or CH(CH ₃ ) ₂ . In some embodiments, each R ^B is independently 3-fluoro-phenyl or CH ₂ CH ₃ . In some embodiments, each R ^B is independently 2-fluoro-phenyl or CH(CH ₃ ) ₂ . In some embodiments, each R ^B is independently 2-fluoro-phenyl or CH ₂ CH ₃ .

In some embodiments, ^CyC is phenylene optionally substituted with 1, 2, 3, or 4 substituents independently selected from ^RC .

In some embodiments, Cy ^C is , wherein the R ^C group on the phenylene ring is located in the ortho position of the pyrro[2,1- f ][1,2,4] triazine ring in formula I.

In some embodiments, each R ^C is independently selected from OH, halo, C _1-4 alkyl, and C _1-3 haloalkyl. In some embodiments, each R ^C is independently halo or C _1-4 alkyl. In some embodiments, each R ^C is independently F, Cl, or methyl. In some embodiments, each R ^C is F.

In some embodiments, Cy ^C is , where R ^C is F, Cl or methyl, where the phenyl ring is connected to the pyrrolo[2,1- f ][1,2,4] triazine ring at the left attachment site.

In some embodiments, Cy ^C is , where R ^C is F, where the phenyl ring is attached to the pyrrolo[2,1- f ][1,2,4] triazine ring at the left attachment site.

In some embodiments, ^R1 is or ; R ^A is CH ₃ , CH ₂ CH ₃ , CN, OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH(CH ₃ ) ₂ , C(O) (Cyclopropyl), C(O)CH ₂ CH ₃ , C(O)CH ₂ OH, C(O)CH(OH)CH ₃ , SO ₂ CH ₃ , C(O)OCH ₃ , C(O) N(CH ₃ ) ₂ , C(O)NHCH ₃ , C(O)N(CH ₂ CH ₃ ) ₂ , C(O)N(CH ₃ )(CH ₂ CH ₃ ) or C(O)(morpholine -4-base); Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Wherein Cy ^B -1, Cy ^B -2 and Cy ^B -3 are each optionally substituted with 1 or 2 substituents independently selected from R ^B ; each R ^B is independently unsubstituted phenyl, 4- F-phenyl, 3-F-phenyl, 2-F-phenyl, 2-pyridyl, CH ₂ (phenyl), CH (phenyl) CH ₂ OH, methyl, ethyl, isopropyl, CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH or OCH ₂ CH ₃ ; Cy ^C is phenylene optionally substituted by 1 R ^C group; and R ^C is F, Cl or Br.

In some embodiments, ^R1 is or ; R ^A is CH ₃ , CH ₂ CH ₃ , CN, OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH ₂ OH, C(O)CH(OH )CH ₃ , SO ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O)NHCH ₃ , C(O)N(CH ₂ CH ₃ ) ₂ or C(O )N(CH ₃ )(CH ₂ CH ₃ ); Cy ^B is or , ^CyB -1 ^CyB -2 Wherein Cy ^B -1 and Cy ^B -2 are each optionally substituted with 1 or 2 substituents independently selected from R ^B ; each R ^B is independently unsubstituted phenyl, 4-F-phenyl, CH ₂ (phenyl), CH(phenyl)CH ₂ OH, methyl, ethyl, CH(CH ₂ OH)CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH or OCH ₂ CH ₃ ; Cy ^C is phenylene optionally substituted with 1 R ^C group; and R ^C is F, Cl or Br.

In some embodiments, ^R1 is or ; R ^A is CH ₃ , CH ₂ CH ₃ , CN, OH, CH ₂ CH ₂ OH, CH ₂ CH ₂ OCH ₃ , C(O)CH ₃ , C(O)CH(CH ₃ ) ₂ , C(O) CH ₂ CH ₃ , C(O)CH ₂ OH , C(O)CH(OH)CH ₃ , SO ₂ CH ₃ , C(O)OCH ₃ , C(O)N(CH ₃ ) ₂ , C(O )NHCH ₃ , C(O)N(CH ₂ CH ₃ ) ₂ , C(O)N(CH ₃ )(CH ₂ CH ₃ ) or C(O)(morpholin-4-yl); Cy ^B is , or , ^CyB -1 ^CyB -2 ^CyB -3 Wherein Cy ^B -1, Cy ^B -2 and Cy ^B -3 are each optionally substituted with 1 or 2 substituents independently selected from R ^B ; each R ^B is independently unsubstituted phenyl, 4- F-phenyl, 3-F-phenyl, 2-F-phenyl, CH ₂ (phenyl), CH (phenyl) CH ₂ OH, methyl, ethyl, isopropyl, CH(CH ₂ OH )CH ₂ CH ₃ , CH(CH ₂ OH)CH ₃ , CH ₂ CH ₂ OH or OCH ₂ CH ₃ ; Cy ^C is phenylene group optionally substituted by 1 R ^C group; and R ^C is F, Cl or Br.

In some embodiments, heteroaryl groups such as Cy ^A and Cy ^B are optionally substituted with pendant oxy groups to form carbonyl groups. For example, the 5 to 10 membered heteroaryl group of Cy ^B may be substituted with pendant oxygen groups to form a carbonyl group including groups such as 2-pyridone, e.g. . Heteroaryl groups may also include substituted pyridones (eg, substituted 2-pyridones), such as and .

In some embodiments: (1) A ¹ , A ² and A ³ are each a bond and R ^A is C _1-6 alkyl, or (2) A ¹ and A ² are each a bond and A ³ is Cy ^A3 and each ^RA is independently selected from C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 and S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by the R ¹¹ group, with the proviso that if ^RA is connected to a nitrogen atom, ^RA is not CN or OR ^a1 ; each R ^a1 , R ^c1 and R ^d1 is independently H or C _1-4 alkyl; each R ^b1 is independently C _1-4 alkyl; each R ¹¹ is independently OR ^a3 ; R ² is H; R ³ is H; Cy ^B is 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring, optionally substituted by 1 or 2 independently selected R ^B groups; each R ^B independently is methyl, ethyl, isopropyl, second butyl or phenyl, each of which is optionally substituted by 1 or 2 independently selected R ¹² groups; each R ¹² is independently selected from halo, phenyl and OR ^a4 ; wherein the phenyl group is optionally substituted with 1 or 2 independently selected R ^g groups; and each R ^g is independently halo; each R ^a4 is independently H or C _1-4 alkyl ; Cy ^C is a phenylene group optionally substituted by 1 R ^C group; and each R ^C is independently a halo group or a C _1-4 alkyl group.

In some embodiments: (1) A ¹ , A ² and A ³ are each a bond and R ^A is methyl or ethyl; or (2) A ¹ and A ² are each a bond and A ^{3 -RA} Department selected from , and ; Each ^RA is independently selected from C _1-3 alkyl, CN, OH, methylcarbonyl, methoxycarbonyl, N,N-dimethylaminocarbonyl and methylsulfonyl, wherein the C _1-3 The alkyl group is optionally substituted with an OH or OCH ₃ group, with the proviso that if ^RA is attached to a nitrogen atom, then ^RA is not CN or OH; R ² is H; R ³ is H; Cy ^B is 7,8- Dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring, which is optionally substituted by an R ^B group; each R ^B is independently methyl, ethyl, isopropyl, A second butyl or phenyl group, each of which is optionally substituted by 1 or 2 independently selected R ¹² groups; each R ¹² is independently selected from halo, phenyl and OH; wherein the phenyl group is optionally substituted by 1 or substituted by 2 independently selected R ^g groups; each R ^g is F; and Cy ^C is , where R ^C is F, where the phenyl ring is attached to the pyrrolo[2,1- f ][1,2,4] triazine ring at the left attachment site.

In some embodiments: A ¹ and A ² are each a bond, and A ³ -R ^A is ; Each R ^A is independently selected from C _1-3 alkyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N ,N-(methyl)(ethyl)aminocarbonyl and C(O)[morpholin-4-yl]; R ² is H; R ³ is H; Cy ^B is 7,8-dihydroquinoline- 2,5(1H,6H)-diketone or 2,4-dilateral oxy-1,2,3,4-tetrahydropyrimidine ring, optionally substituted by 1 or 2 independently selected R ^B groups ; Each R ^B is independently methyl, ethyl, isopropyl, second butyl or phenyl, each of which is optionally substituted by 1 or 2 independently selected R ¹² groups; each R ¹² is independently Selected from halo; and Cy ^C is unsubstituted phenylene.

In some embodiments, the disclosure provides compounds of Formula (IIa): IIa or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIa) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the disclosure provides compounds of Formula (IIa1) or Formula (IIa2): IIa1 IIa2 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIa1) and formula (IIa2) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of Formula (IIb1) or Formula (IIb2): IIb1 IIb2 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIb1) and formula (IIb2) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the disclosure provides compounds of Formula (IIc1) or Formula (IIc2): IIc1 IIc2 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIc1) and formula (IIc2) are as defined in formula (I) or in any embodiment of a compound of formula (I) as described herein.

In some embodiments, the disclosure provides compounds of Formula (IId1) or Formula (IId2): IId1 IId2 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IId1) and formula (IId2) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of formula (IIe1): IIe1 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIe1) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of Formula (IIf1) or Formula (IIf2): IIf1 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIlf1) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of Formula (IIg1) or Formula (IIg2): IIg1 IIg2 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIg1) and formula (IIg2) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the invention provides compounds of formula (IIg3), formula (IIg4), and formula (IIg5): IIg3 IIg4 IIg5 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIg3), formula (IIg4) and formula (IIg5) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein, and t is 0, 1, 2, 3 or 4.

In some embodiments, the present disclosure provides compounds of formula (IIh1): h1 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIh1) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of formula (IIi1): IIi1 or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIi1) are as defined in formula (I) or in any embodiment of a compound of formula (I) described herein.

In some embodiments, the present disclosure provides compounds of Formula (IIIa), Formula (IVa), Formula (Va), Formula (VIa), Formula (VIIa), or Formula (VIIIa): , , , IIIa IVa Va , or , VIa VIIa VIIIa Or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIIa), formula (IVa), formula (Va), formula (VIa), formula (VIIa) and formula (VIIIa) are as in formula (I) or as described herein as defined in any embodiment of the compound of formula (I).

In some embodiments, the present disclosure provides compounds of Formula (IIIb), Formula (IVb), Formula (Vb), Formula (VIb), Formula (VIIb), or Formula (VIIIb): , , , IIIb IVb Vb , or , VIb VIIb VIIIb Or a pharmaceutically acceptable salt thereof, wherein the variables of formula (IIIb), formula (IVb), formula (Vb), formula (VIb), formula (VIIb) and formula (VIIIb) are as in formula (I) or as herein as defined in any embodiment of the compound of formula (I).

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H, halo, CN, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 Alkoxy, C _1-4 haloalkoxy, cyano-C _1-3 alkyl or C _1-6 alkoxyalkyl; R ³ is H, halo, CN, C _1-6 alkyl, C _1-6 haloalkyl, OR ^a , SR ^a , C(O)NR ^c R ^d , NR ^c R ^d , NR ^c C(O)R ^b , NR ^c S(O) ₂ R ^b or S(O ) ₂ R ^b ; wherein the C _1-6 alkyl group and C _1-6 haloalkyl group are independently selected from halo group, CN, OR ^a , SR ^a , C(O)NR via 1, 2 or 3 as appropriate. ^c R ^d , NR ^c R ^d , NR ^{c C} (O)R ^b , NR ^c S(O) ₂ R ^b , S(O) ₂ R ^b , NR ^c C(O)OR ^a , NR ^c C(O )NR ^c R ^d , NR ^c S(O) ₂ NR ^c R ^d and Cy ^R3 are substituted by substituents; A ¹ is selected from one bond, Cy ^A1 , -Y-, -C _1-3 alkylene-, -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 alkylene-YC _1-2 alkylene-; wherein each of these alkylene groups is optionally 1, 2 or 3 independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, amine Substituted with substituents of base, C _1-3 alkylamino group and di(C _1-3 alkyl)amine group; A ² is selected from one bond, Cy ^A2 , -Y-, -C _1-3 alkyl- , -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 alkylene-YC _1-2 alkylene-; wherein each of these alkylene groups is as appropriate 1, 2 or 3 independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy, Substituted by substituents of amine group, C _1-3 alkylamino group and di(C _1-3 alkyl)amine group; A ³ is selected from one bond, Cy ^A3 , -Y-, -C _1-3 alkyl alkylene group -, -C _1-3 alkylene-Y-, -YC _1-3 alkylene- and -C _1-2 alkylene-YC _1-2 alkylene-; wherein each of these alkylene groups is regarded as 1, 2 or 3 cases are independently selected from halo, CN, OH, C _1-3 alkyl, C _1-3 alkoxy, C _1-3 haloalkyl, C _1-3 haloalkoxy , amino group, C _1-3 alkylamino group and di(C _1-3 alkyl) amino group substituent substitution; R ^A is H, C _1-6 alkyl group, C _1-6 haloalkyl group, halo group ,CN,NO ₂ ,OR ^a1 ,SR ^a1 ,C(O)R ^b1 ,C(O)NR ^c1 R ^d1 ,C(O)OR ^a1 ,OC(O)R ^b1 ,OC(O)NR ^c1 R ^d1 ,NR ^c1 R ^d1 ,NR ^c1 OR ^d1 ,NR ^c1 C(O)R ^b1 ,NR ^c1 C(O)OR ^a1 ,NR ^c1 C(O)NR ^c1 R ^d1 ,C(=NR ^e1 )R ^b1 ,C (=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 C(=NR ^e1 )NR ^c1 R ^d1 , NR ^c1 S(O)R ^b1 , NR ^c1 S(O) ₂ R ^b1 , NR ^c1 S(O) ₂ NR ^c1 R ^d1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl or C _{1- 6} Haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; Y is O, S, S(O), S(O) ₂ , C(O), C( O)NR ^f , NR ^f C(O), NR ^f C(O)NR ^f , NR ^f S(O) ₂ NR ^f , S(O) ₂ NR ^f , NR ^f S(O) ₂ or NR ^f ; Each R ^f is independently selected from H and C _1-3 alkyl; Cy ^A1 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; where each Each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S is optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxy groups to form carbonyl groups; and wherein C _3-7 cycloalkyl, Phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R ^A1 ; each R ^A1 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl Base, HO-C _1-3 alkyl group, H ₂ NC _1-3 alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _1-6 Alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl) Aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylsulfonylamine group, aminosulfonylamine group , C _1-6 alkylaminosulfonyl group, two (C _1-6 alkyl) aminosulfonylamine group, aminosulfonylamine group, C _1-6 alkylaminosulfonylamine group, two ( C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^A2 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; wherein each 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl has at least one Ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are oxidized as appropriate; wherein C _3-7 cycloalkyl and 4 to 7 members The ring-forming carbon atoms of the heterocycloalkyl group are optionally substituted with pendant oxygen groups to form a carbonyl group; and among them, C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each Optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A2 ; each R ^A2 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _{1- 6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, Amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 alkyl group Sulfonyl group, aminoformyl group, C _1-6 alkylamineformyl group, di(C _1-6 alkyl)aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkyl group Oxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, aminosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl )Aminosulfonylamine, C 1-6 alkylaminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino , C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^A3 is C _3-7 cycloalkyl, phenyl, 5 to 6-membered heteroaryl or 4 to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 independently selected from N, O and the ring-forming heteroatoms of S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl groups; And wherein C _3-7 cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl are each optionally subject to 1, 2, 3 or 4 substituents independently selected from R ^A3 Substitution; Each R ^A3 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy group, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amine, C _1-6 alkylamino, di(C _1-6 alkyl) Amino group, thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, aminoformyl group, C _1-6 alkylamineformyl group , di(C _1-6 alkyl)amine methanoyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonyl Amino group, aminosulfonyl group, C _1-6 alkylaminosulfonyl group, di(C _1-6 alkyl) aminosulfonyl group, aminosulfonylamine group, C _1-6 alkyl Aminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl) )Aminocarbonylamino; Cy ^R3 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; wherein each 5 to 6 membered heteroaryl and 4 The 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein C ₃ The ring-forming carbon atoms of _-7 cycloalkyl and 4- to 7-membered heterocycloalkyl are optionally substituted with pendant oxy groups to form carbonyl groups; and among them, C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; Cy ^C is phenyl or 5- to 6-membered heteroaryl; where 5 The 6- to 6-membered heteroaryl group has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S; and wherein the phenylene group and the 5- to 6-membered heteroaryl group each represent The case is substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently selected from OH, CN, halo, C _1-4 alkyl, C _1-3 haloalkyl , C _1-4 alkoxy, C _1-3 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, amino, C _1-4 alkylamino, di( C _1-4 alkyl)amine group, C _1-4 alkyl sulfinyl group, C _1-4 alkyl sulfonyl group, amine methyl group, C _1-4 alkyl amine methyl group, di(C _1-4 alkyl)aminoformyl, carboxyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamine , aminosulfonyl group, C _1-4 alkylaminosulfonyl group and di(C _1-4 alkyl) aminosulfonyl group; Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycle Alkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl is substituted by a pendant oxygen group to form a carbonyl group; wherein 4 to 10 membered heterocycloalkyl has at least one ring carbon atom Carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein C _3-10 cycloalkyl and 4 to 10 membered heteroatoms Each cycloalkyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; or Cy ^B is a 5 to 10 membered heteroaryl group; wherein the 5 to 10 membered heteroaryl group has at least one Ring carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein: (a) at least 5 to 10 membered heteroaryl groups One ring-forming carbon atom is substituted by a pendant oxygen group to form a carbonyl group; or (b) a 5 to 10-membered heteroaryl group is substituted by a halo group, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O )NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR c2 R ^d2 , NR ^c2 OR ^d2 , ^{NR c2 C} (O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S (O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 are substituted; and the 5 to 10-membered heteroaryl group is optionally replaced by 1, 2, 3 or 4 substituents independently selected from R ^B are further substituted; each R ^B is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, Phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O )OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O )NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl group and 4- to 7-membered heterocycloalkyl groups are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ¹¹ is independently selected from CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 OR ^d3 ,NR ^c3 C(O)R ^b3 ,NR ^c3 C(O)OR ^a3 ,NR ^c3 C(O)NR ^c3 R ^d3 ,NR ^c3 S(O)R ^b3 ,NR ^c3 S(O) ₂ R ^b3 ,NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ¹² is independent is selected from halo, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heteroaryl Cycloalkyl, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 OR ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 C(O)NR ^c4 R ^d4 , NR ^c4 S(O)R ^b4 , NR ^c4 S (O) ₂ R ^b4 , NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl are each represented by 1, 2, 3 or 4 as appropriate Substituted with a substituent independently selected from R ^g ; R ^a is selected from H, C _1-6 alkyl and C _1-6 haloalkyl; R ^b is selected from C _1-6 alkyl and C _1-6 Haloalkyl; R ^c and R ^d are each independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4 to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-3 alkylene, phenyl-C _1-3 alkylene, 5 to 6-membered heteroaryl-C _1-3 alkylene and 4 to 6 membered heterocycloalkyl-C _1-3 alkylene group; wherein the C _1-6 alkyl group, C _1-6 haloalkyl group, C _3-6 cycloalkyl group, phenyl group, 5 to 6 Member heteroaryl, 4- to 6-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-3 alkylene, phenyl-C _1-3 alkylene, 5- to 6-membered heteroaryl-C Each of the _1-3 alkylene group and the 4- to 6-membered heterocycloalkyl-C _1-3 alkylene group is optionally substituted with 1, 2 or 3 substituents independently selected from ^Rg ; R ^a1 , R ^c1 and R ^d1 is each independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally selected from 1, 2, 3 or 4 of R ^g Substituted with substituents; or alternatively, R ^c1 and R ^d1 attached to the same N atom together with the N atom to which they are attached form 4, 5 optionally substituted with 1, 2 or 3 substituents independently selected from R ^g , 6- or 7-membered heterocycloalkyl; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is independently selected from R ^g by 1, 2, 3 or 4 as appropriate. Substituent substitution; R ^e1 is selected from H, CN, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkylthio, C _1-6 alkylsulfonyl, C _1-6 Alkylcarbonyl, C _1-6 alkylamino sulfonyl, amine methyl, C _1-6 alkyl amine methyl, di(C _1-6 alkyl) amine methyl, amine sulfonyl , C _1-6 alkylaminosulfonyl group and di(C _1-6 alkyl)aminosulfonyl group; each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl; wherein the C _1-6 alkyl, C _3-6 ring Alkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; or alternatively, connected to Any R ^c2 and R ^d2 of the same N atom together with the N atom to which they are attached form a 4, 5, 6 or 7-membered heterocycloalkane, optionally substituted with 1, 2 or 3 substituents independently selected from R ¹² group; each R ^b2 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycle Alkyl, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Each R ^a3 , R ^c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene base, phenyl-C _1-4 alkylene group, 5- to 6-membered heteroaryl-C _1-4 alkylene group and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene group; wherein the C _{1 -6} alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl -C _1-4 alkylene, phenyl The base-C _1-4 alkylene group, the 5- to 6-membered heteroaryl-C _1-4 alkylene group, and the 4- to 7-membered heterocycloalkyl-C _1-4 alkylene group are each optionally passed through 1, 2, Substituted with 3 or 4 substituents independently selected from R ^g ; or alternatively, any R ^c3 and R ^d3 connected to the same N atom together with the N atom to which they are connected are formed by 1, 2 or 3 independently 4, 5, 6 or 7-membered heterocycloalkyl substituted by a substituent selected from R ^g ; each R ^b3 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 ring Alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6 membered heteroaryl-C _1-4 alkylene and 4 to 7 membered heterocycloalkyl-C _1-4 alkylene, each of which is independently selected from 1, 2, 3 or 4 as appropriate. R ^g is substituted with a substituent; each R ^a4 , R ^c4 and R ^d4 are independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally replaced by 1 , 2, 3 or 4 substituted with substituents independently selected from R ^g ; or alternatively, any R ^c4 and R ^d4 connected to the same N atom together with the N atom to which they are connected form a chain via 1, 2 or 3 as appropriate. are independently selected from 4, 5, 6 or 7-membered heterocycloalkyl substituted by the substituent of R ^g ; each R ^b4 is independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which Optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; and each R ^g is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _{1 -6} haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl , Amino group, C _1-6 alkylamino group, di(C _1-6 alkyl) amino group, thio group, C _1-6 alkylthio group, C _1-6 alkylsulfinyl group, C _1-6 Alkyl sulfonyl, aminoformyl, C _1-6 alkylamineformyl, di(C _1-6 alkyl)amineformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 Alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, amidosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl base) aminosulfonylamine, aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamine group, C _1-6 alkylaminocarbonylamino group and di(C _1-6 alkyl)aminocarbonylamino group; the restrictions are: 1) When one of A ¹ , A ² or A ³ is a bond or When YYY, A ¹ -A ² -A ³ is not YY; and 2) When A ³ is -Y- or -C _1-3 alkyl-Y-, then R ^A is H, C _1-6 alkyl Or C _1-6 haloalkyl, wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H, halo, CN, C _1-4 alkyl or C _1-4 haloalkyl; R ³ is H , halo group, CN, C _1-6 alkyl or C _1-6 haloalkyl; A ¹ is selected from one bond, Cy ^A1 , -Y-, -C _1-3 alkylene-, -C _{1- 3} Alkylene-Y- and -YC _1-3 Alkylene-; A ² is selected from one bond, Cy ^A2 , -Y-, -C _1-3 Alkylene-, -C _1-3 Alkylene -Y- and -YC _1-3 alkylene-; A ³ is selected from one bond, Cy ^A3 , -Y-, -C _1-3 alkylene-, -C _1-3 alkylene-Y -and-YC _1-3 alkylene-; R ^A is H, C _1-6 alkyl, C _1-6 haloalkyl, halo, CN, NO ₂ , OR ^a1 , SR ^a1 , C(O) R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , OC(O)R ^b1 , OC(O)NR c1 R d1 , NR ^{c1 R d1 , NR c1 C} (O)R ^b1 , NR ^c1 C(O)OR ^a1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl group Or C _1-6 haloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; Y is O, S, S(O), S(O) ₂ or C(O ); Cy ^A1 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; wherein each 5 to 6 membered heteroaryl and 4 to 7 membered heterocycle The alkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein C _3-7 cycloalkyl And the ring-forming carbon atoms of 4- to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; and among them, C _3-7 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heteroaryl Each heterocycloalkyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A1 ; each R ^A1 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl group, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _{1 -3} alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl) amino group, sulfo group, C _1-6 alkylthio group, C _1-6 alkyl sulfenyl group, C _1-6 alkyl sulfonyl group, aminoformyl group, C _1-6 alkyl aminoformyl group, di(C _1-6 alkyl) aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine, aminosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, Aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl)aminocarbonylamino; Cy ^A2 is C _3-7 cycloalkyl, phenyl, 5 to 6 members Heteroaryl or 4- to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 independently Ring-forming heteroatoms selected from N, O and S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally oxidized through pendant oxy groups Substituted to form carbonyl; and wherein each of C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl is independently selected from 1, 2, 3 or 4 as appropriate. The substituents of R ^A2 are substituted; each R ^A2 is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _{1 -6} haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _1-6 alkylamino, di(C _{1 -6} alkyl) amino group, thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl group Aminoformyl, di(C _1-6 alkyl)amineformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _{1 -6} alkylsulfonylamine, amidosulfonyl, C _1-6 alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl, amidosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl)aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and di(C _1-6 alkyl) aminocarbonylamino; Cy ^A3 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl; each of which has 5 to 6 members Heteroaryl and 4- to 7-membered heterocycloalkyl have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally Oxidation; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; and wherein C _3-7 cycloalkyl, phenyl, 5 to Each of the 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A3 ; each R ^A3 is independently selected from OH, NO ₂ , CN _, halo, C _1-6 alkyl, C _{1-6 haloalkyl, C 1-6} alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl group, H ₂ NC _1-3 alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl)amine group, thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl) amine methyl group, Carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylsulfonylamine group, aminosulfonylamine group, C _1-6 Alkylaminosulfonyl, di(C _1-6 alkyl)aminosulfonyl, aminosulfonylamine, C _1-6 alkylaminosulfonylamine, di(C _1-6 alkyl) base) aminosulfonylamine group, aminocarbonylamino group, C _1-6 alkylaminocarbonylamino group and di(C _1-6 alkyl)aminocarbonylamino group; Cy ^C is phenylene group or 5 to a 6-membered heteroaryl group; wherein the 5- to 6-membered heteroaryl group has at least one ring-forming carbon atom and 1 or 2 ring-forming heteroatoms independently selected from N, O, and S; and wherein the phenylene group and Each of the 5- to 6-membered heteroaryl groups is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently selected from OH, CN, halo, C _1-4 Alkyl, C _1-3 haloalkyl, C _1-4 alkoxy, C _1-3 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, amine, C _1-4 alkylamino group, di(C _1-4 alkyl)amine group, C _1-4 alkyl sulfonyl group, C _1-4 alkyl sulfonyl group, aminomethanoyl group, C _1-4 Alkylamineformyl, di(C _1-4 alkyl)amineformyl, carboxyl, C _1-4 alkylcarbonyl, C _1-4 alkoxycarbonyl, C _1-4 alkylcarbonylamino, C _1-4 alkylsulfonylamine, amidosulfonyl, C _1-4 alkylaminosulfonyl and di(C _1-4 alkyl)aminosulfonyl; Cy ^B is C _3-10 Cycloalkyl or 4 to 10-membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10-membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein 4 to 10 The membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein C _{3- 10-} cycloalkyl and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; or Cy ^B is 6 to 10-membered aryl or 5 to 10 Member heteroaryl; wherein 5 to 10 membered heteroaryl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optional Oxidized; wherein: (a) at least one ring carbon atom of the 5- to 10-membered heteroaryl group is substituted with a pendant oxygen group to form a carbonyl group; or (b) the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group is Halogen group, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , OC(O)R ^b2 , OC(O)NR ^c2 R ^d2 , NR ^c2 R ^d2 , NR ^c2 OR ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 C(O)OR ^a2 , NR ^c2 C(O)NR ^c2 R ^d2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O ) ₂ NR ^c2 R ^d2 substituted; and wherein the 6- to 10-membered aryl group or the 5- to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; each R ^B is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl ,CN,NO ₂ ,OR ^a2 ,SR ^a2 ,C(O)R ^b2 ,C(O)NR ^c2 R ^d2 ,C(O)OR ^a2 ,OC(O)R ^b2 ,OC(O)NR ^c2 R ^d2 ,NR ^c2 R ^d2 ,NR ^c2 OR ^d2 ,NR ^c2 C(O)R ^b2 ,NR ^c2 C(O)OR ^a2 ,NR ^c2 C(O)NR ^c2 R ^d2 ,NR ^c2 S(O)R ^b2 ,NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl are each represented by 1, 2, 3 as appropriate Or substituted by 4 substituents independently selected from R ¹² ; each R ¹¹ is independently selected from CN, NO ₂ , OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C (O)OR ^a3 , OC(O)R ^b3 , OC(O)NR ^c3 R ^d3 , NR ^c3 R ^d3 , NR ^c3 OR ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 C(O)NR ^c3 R ^d3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S(O)R ^b3 , S (O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, CN, NO ₂ , C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, OR ^a4 , SR ^a4 , C(O)R ^b4 , C( O)NR ^c4 R ^d4 , C(O)OR ^a4 , OC(O)R ^b4 , OC(O)NR ^c4 R ^d4 , NR ^c4 R ^d4 , NR ^c4 OR ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 C(O)NR ^c4 R ^d4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O) ₂ R ^b4 , NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C _1-6 alkyl and C _3-6 cycloalkyl , phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; R ^a1 , R ^c1 and R ^d1 is each independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 independently selected from R ^g or ^, alternatively, R ^c1 and R ^d1 connected to the same N atom together with the N atom to which they are connected form 4, 5, 4, 5, 6 or 7-membered heterocycloalkyl; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R ^g Substituted with a base; each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered hetero Aryl and 4 to 7-membered heterocycloalkyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl are each considered substituted by 1, 2, 3 or 4 substituents independently selected from R ¹² ; or alternatively, any R ^c2 and R ^d2 attached to the same N atom together with the N atom to which they are attached form, as the case may be, 1, 2 or 3 4, 5, 6 or 7-membered heterocycloalkyl substituted with substituents independently selected from R ¹² ; each R ^b2 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl , C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl, each of which is optionally substituted by 1, 2, 3 or 4 independently selected from R ¹² group substitution; each R ^a3 , R ^c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered hetero Aryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5- to 6-membered heteroaryl-C _{1- 4-} alkylene and 4- to 7-membered heterocycloalkyl-C _1-4 alkylene; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl, 4 to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6-membered heteroaryl-C _1-4 alkylene group and the 4- to 7-membered heterocycloalkyl-C _1-4 alkylene group are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; or alternatively, attached to the same N atom Any R ^c3 and R ^d3 together with the N atom to which they are attached form a 4, 5, 6 or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ^g ; each R ^b3 is independently selected from C _1-6 alkyl, C _{1-6 haloalkyl, C 3-6 cycloalkyl} , phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6-membered heteroaryl-C _1-4 alkylene and 4 to 7-membered heterocycloalkyl -C _1-4 alkylene, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; each R ^a4 , R ^c4 and R ^d4 are independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from ^Rg ; or alternatively, connected to the same Any R ^c4 and R ^d4 of N atoms together with the N atom to which they are attached form a 4, 5, 6 or 7-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 substituents independently selected from R ^g ; Each R ^b4 is independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; and each Each ^Rg is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano Base-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _1-6 alkylamino, di(C _1-6 alkyl)amine, Thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di( C _1-6 alkyl)aminoformyl, carboxyl, C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, C _1-6 alkylcarbonylamino, C _1-6 alkylsulfonylamine base, amidosulfonyl group, C _1-6 alkylaminosulfonyl group, di(C _1-6 alkyl) amidosulfonyl group, amidosulfonylamine group, C _1-6 alkylaminosulfonyl group Cylamine group, di(C _1-6 alkyl)aminosulfonylamine group, aminocarbonylamino group, C _1-6 alkylaminocarbonylamino group and di(C _1-6 alkyl)amine group Carbonylamine group; The limitations are: 1) When one of A ¹ , A ² or A ³ is a bond or YYY, A ¹ -A ² -A ³ is not YY; and 2) When A ³ is -Y- or -C _1-3 alkylene-Y-, then R ^A is H, C _1-6 alkyl or C _1-6 haloalkyl, wherein the C _1-6 alkyl or C _1-6 haloalkyl The group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^R11 .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H, halo or C _1-4 alkyl; R ³ is H, halo or C _1-6 alkyl ; A ¹ is selected from one bond, -Y- and -C _1-3 alkylene-; A ² is selected from one bond, -Y- and -C _1-3 alkylene-; A ³ is selected from One bond, Cy ^A3 , -Y- and -C _1-3 alkylene-; R ^A is H, C _1-6 alkyl, C _1-6 haloalkyl, halo, CN, OR ^a1 , SR ^a1 ,C(O)R ^b1 ,C(O)NR ^c1 R ^d1 ,C(O)OR ^a1 ,NR ^c1 R ^d1 ,NR ^c1 C(O)R ^b1 ,S(O)R ^b1 ,S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl or C _1-6 haloalkyl group undergoes 1, 2, 3 or 4 independent is substituted with a substituent selected from R ¹¹ ; Y is O, S, S(O), S(O) ₂ or C(O); Cy ^A3 is C _3-7 cycloalkyl, phenyl, 5 to 6 members Heteroaryl or 4- to 7-membered heterocycloalkyl; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 independently Ring-forming heteroatoms selected from N, O and S; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally oxidized through pendant oxy groups Substituted to form carbonyl; and wherein each of C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl is independently selected from 1, 2, 3 or 4 as appropriate. The substituents of R ^A3 are substituted; each R ^A3 is independently selected from OH, CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 halo Alkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amine, C _1-6 alkylamino, di(C _1-6 alkyl Base) amino group, thio group, C _1-6 alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group acyl group, bis(C _1-6 alkyl)aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group and C _1-6 alkoxycarbonyl group; Cy ^C is phenylene group, in which the phenylene group is optionally replaced by 1 , 2, 3 or 4 substituted with substituents independently selected from R ^C ; Each R ^C is independently selected from OH, CN, halo, C _1-4 alkyl, C _1-3 haloalkyl, C _{1 -4} alkoxy, C _1-3 haloalkoxy, cyano -C _1-3 alkyl, HO-C _1-3 alkyl, amino, C _1-4 alkylamino and di(C _{1- 4} alkyl) amino group; Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein at least one ring-forming carbon of C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl The atom is substituted by a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; and wherein C _3-10 cycloalkyl and 4 to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^RB ; Or Cy ^B is a 6- to 10-membered aryl group or a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 independently selected from N, O and ring-forming heteroatoms of S; wherein N and S are optionally oxidized; wherein at least one ring-forming carbon atom of the 5- to 10-membered heteroaryl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 6- to 10-membered aryl group or The 5 to 10 membered heteroaryl is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; each R ^B is independently selected from halo, C _1-6 alkyl, C _{1 -6} haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl, CN, NO ₂ , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , C(O)OR ^a2 , NR ^c2 R ^d2 , NR ^c2 C(O)R ^b2 , NR ^c2 S(O)R ^b2 , NR ^c2 S(O) ₂ R ^b2 , NR ^c2 S(O) ₂ NR ^c2 R ^d2 , S(O)R ^b2 , S(O)NR ^c2 R ^d2 , S(O) ₂ R ^b2 and S(O) ₂ NR ^c2 R ^d2 ; where the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl are each independently selected from R via 1, 2, 3 or 4 as appropriate. ¹² is substituted with a substituent; each R ¹¹ is independently selected from CN, OR ^a3 , SR ^a3 , C(O)R ^b3 , C(O)NR ^c3 R ^d3 , C(O)OR ^a3 , NR ^c3 R ^d3 , NR ^c3 C(O)R ^b3 , NR ^c3 C(O)OR ^a3 , NR ^c3 S(O)R ^b3 , NR ^c3 S(O) ₂ R ^b3 , NR ^c3 S(O) ₂ NR ^c3 R ^d3 , S (O)R ^b3 , S(O)NR ^c3 R ^d3 , S(O) ₂ R ^b3 and S(O) ₂ NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, CN, C _1-6 Alkyl group, C _1-6 haloalkyl group, C _3-6 cycloalkyl group, phenyl group, 5 to 6 membered heteroaryl group, 4 to 7 membered heterocycloalkyl group, OR ^a4 , SR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 , C(O)OR ^a4 , NR ^c4 R ^d4 , NR ^c4 C(O)R ^b4 , NR ^c4 C(O)OR ^a4 , NR ^c4 S(O)R ^b4 , NR ^c4 S(O) ₂ R ^b4 , NR ^c4 S(O) ₂ NR ^c4 R ^d4 , S(O)R ^b4 , S(O)NR ^c4 R ^d4 , S(O) ₂ R ^b4 and S(O) ₂ NR ^c4 R ^d4 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5- to 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl are each passed through 1, 2, 3 or 4 substituted substituents independently selected from R ^g ; R ^a1 , R ^c1 and R ^d1 are each independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _{1- 6} alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted. 1, 2, 3 or 4 substituted substituents independently selected from R ^g ; Each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl, 5 to 7 Each of the 6-membered heteroaryl and the 4- to 7-membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ^b2 is independently selected from C _1-6 alkane base, C _1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl and 4 to 7 membered heterocycloalkyl, each of which is optionally represented by 1, 2, 3 or 4 Substituted with a substituent independently selected from R ¹² ; each R ^a3 , R ^c3 and R ^d3 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl , phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6-membered heteroaryl-C _1-4 alkylene and 4 to 7-membered heterocycloalkyl-C _1-4 alkylene; wherein the C _1-6 alkyl, C _3-6 cycloalkyl, phenyl , 5 to 6-membered heteroaryl, 4 to 7-membered heterocycloalkyl, C _3-6 cycloalkyl-C _1-4 alkylene, phenyl-C _1-4 alkylene, 5 to 6-membered hetero Aryl-C _1-4 alkylene and 4 to 7-membered heterocycloalkyl-C _1-4 alkylene are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; Each R ^b3 is independently selected from C _1-6 alkyl _, C 1-6 haloalkyl, C _3-6 cycloalkyl, phenyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl , C _3-6 cycloalkyl-C _1-4 alkylene group, phenyl-C _1-4 alkylene group, 5 to 6 membered heteroaryl-C _1-4 alkylene group and 4 to 7 membered heterocycle Alkyl-C _1-4 alkylene, each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; each R ^a4 , R ^c4 and R ^d4 is independently selected from H , C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^b4 independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; and each R ^g is independently selected Selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano -C _{1- 3} alkyl group, HO-C _1-3 alkyl group, H ₂ NC _1-3 alkyl group, amino group, C _1-6 alkylamino group, di(C _1-6 alkyl) amino group, thio group, C _{1 -6} alkylthio group, C _1-6 alkyl sulfinyl group, C _1-6 alkyl sulfonyl group, amine methyl group, C _1-6 alkyl amine methyl group, di(C _1-6 alkyl group Base) Aminoformyl group, carboxyl group, C _1-6 alkylcarbonyl group, C _1-6 alkoxycarbonyl group, C _1-6 alkylcarbonylamino group, C _1-6 alkylsulfonylamine group, amine sulfonyl group acyl group, C _1-6 alkylaminosulfonylamine group, di(C _1-6 alkyl)aminosulfonylamine group, aminesulfonylamine group, C _1-6 alkylaminosulfonylamine group, Two (C _1-6 alkyl) aminosulfonylamine, aminocarbonylamino, C _1-6 alkylaminocarbonylamino and two (C _1-6 alkyl) aminocarbonylamino; The restrictions are: 1) When one of A ¹ , A ² or A ³ is a key or YYY, A ¹ -A ² -A ³ is not YY; and 2) When A ³ is -Y- or -C _1- When ₃ alkylene-Y-, then R ^A is H, C _1-6 alkyl or C _1-6 haloalkyl, wherein the C _1-6 alkyl or C _1-6 haloalkyl is optionally replaced by 1 , 2, 3 or 4 substituted with substituents independently selected from R ¹¹ .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} ; R ² is H or C _1-4 alkyl; R ³ is H or C _1-6 alkyl; A ¹ is selected from One bond and -C _1-3 alkylene-; A ² is selected from one bond and -C _1-3 alkylene-; A ³ is selected from one bond, Cy ^A3 and -C _1-3 alkylene- -; R ^A is H, C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 , NR ^c1 R ^d1 , NR ^c1 C (O)R ^b1 , S(O)R ^b1 , S(O)NR ^c1 R ^d1 , S(O) ₂ R ^b1 or S(O) ₂ NR ^c1 R ^d1 ; wherein the C _1-6 alkyl group depends on the situation Substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; Cy ^A3 is C _3-7 cycloalkyl, phenyl, 5 to 6 membered heteroaryl or 4 to 7 membered heterocycloalkyl ; wherein each 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S ; wherein N and S are optionally oxidized; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with side oxygen groups to form carbonyl; and wherein C _3-7 ring Alkyl, phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^A3 ; each R ^A3 is independently is selected from OH, CN, halo, C _1-6 alkyl, C _1-6 haloalkyl and C _1-6 alkoxy; Cy ^C is a phenyl group, in which the phenyl group is optionally passed through 1, 2 , 3 or 4 substituted with substituents independently selected from R ^C ; Each R ^C is independently selected from OH, CN, halo, C _1-4 alkyl, C _1-3 haloalkyl, C _1-4 Alkoxy and C _1-3 haloalkoxy; Cy ^B is C _3-10 cycloalkyl or 4 to 10 membered heterocycloalkyl; wherein C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl At least one ring-forming carbon atom is substituted with a pendant oxygen group to form a carbonyl group; wherein the 4- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 independently selected from N, O and S of ring-forming heteroatoms; wherein N and S are optionally oxidized; and wherein C _3-10 cycloalkyl and 4 to 10-membered heterocycloalkyl are each optionally independently selected from R ^B is substituted by a substituent; or Cy ^B is a 5- to 10-membered heteroaryl group; wherein the 5- to 10-membered heteroaryl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 independently selected from N, O and Ring-forming heteroatoms of S; wherein N and S are optionally oxidized; wherein at least one ring-forming carbon atom of the 5- to 10-membered heteroaryl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heteroaryl group is optionally The case is further substituted by 1, 2, 3 or 4 substituents independently selected from R ^B ; each R ^B is independently selected from halo, C _1-6 alkyl, C _1-6 haloalkyl, phenyl , OR ^a2 , SR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 and C(O)OR ^a2 ; wherein the C _1-6 alkyl group and phenyl group are each passed through 1, 2, 3 as appropriate. Or substituted by 4 substituents independently selected from R ¹² ; Each R ¹¹ is independently selected from CN or OR ^a3 ; Each R ¹² is independently selected from halo, CN, C _1-6 alkyl, C _{1- 6} haloalkyl, phenyl, OR ^a4 , C(O)R ^b4 , C(O)NR ^c4 R ^d4 and C(O)OR ^a4 ; wherein the C _1-6 alkyl, C _3-6 cycloalkyl , phenyl, 5- to 6-membered heteroaryl and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from ^Rg ; R ^a1 , R ^c1 and R ^d1 is each independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally substituted by 1, 2, 3 or 4 independently selected from R ^g substituted; R ^b1 is selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^g ; each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl and phenyl; wherein the C _1-6 alkyl and phenyl are each optionally passed through 1, 2, 3 or 4 substituted substituents independently selected from R ¹² ; each R ^b2 is independently selected from C _1-6 alkyl, C _1-6 haloalkyl, C _3-6 cycloalkyl and phenyl, which Each is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; each R ^a3 is independently selected from H, C _1-6 alkyl, C _1-6 haloalkyl, phenyl , phenyl-C _1-4 alkylene; wherein the C _1-6 alkyl, phenyl and phenyl-C _1-4 alkylene are each independently selected from 1, 2, 3 or 4 as appropriate. R ^g is substituted with a substituent; each R ^a4 , R ^c4 and R ^d4 are independently selected from H, C _1-6 alkyl and C _1-6 haloalkyl; wherein the C _1-6 alkyl is optionally replaced by 1 , 2, 3 or 4 substituted with substituents independently selected from ^Rg ; Each R ^b4 is independently selected from C _1-6 alkyl and C _1-6 haloalkyl, each of which is optionally replaced by 1, 2, 3 or 4 substituents independently selected from R ^g are substituted; and each R ^g is independently selected from OH, NO ₂ , CN, halo, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 haloalkoxy, cyano-C _1-3 alkyl, HO-C _1-3 alkyl, H ₂ NC _1-3 alkyl, amino, C _{1- 6-} alkylamine group and di(C _1-6 alkyl)amine group.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein each of A ¹ , A ² and A ³ is a bond and ^RA is C _1-6 alkyl or C (O)NR ^c1 R ^d1 , (2) wherein A ¹ is a bond, A ² is a bond or -C _1-3 alkyl-, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl , CN, OR ^a1 , NR ^c1 R ^d1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; where C _1- of R ^A ₆ The alkyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ , or (3) where A ¹ is Cy ^A1 , A ² is a bond or C(O), and A ³ is Cy ^A3 and R ^A is H; R ² is H; R ³ is H; Cy ^A1 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one Ring-forming carbon atoms and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are oxidized as appropriate; wherein C _3-7 cycloalkyl and 4 to 7 members The ring-forming carbon atoms of the heterocycloalkyl group are optionally substituted with pendant oxygen groups to form carbonyl groups; Cy ^A3 is C _3-7 cycloalkyl, 6-membered heteroaryl or 4 to 7-membered heterocycloalkyl; wherein each 6 The membered heteroaryl group and the 4- to 7-membered heterocycloalkyl group have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optional After oxidation; wherein the ring carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl groups; and wherein C _3-7 cycloalkyl, 6-membered heteroaryl The base and the 4- to 7-membered heterocycloalkyl group are each optionally substituted with 1, 2, 3 or 4 C _1-6 alkyl groups; Cy ^B is a C _3-10 cycloalkyl group or a 4 to 10-membered heterocycloalkyl group; wherein at least one ring-forming carbon atom of C _3-10 cycloalkyl and 4- to 10-membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein 4- to 10-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and among them, C _3-10 cycloalkyl and 4 to 10 membered heterocycloalkyl are each optionally separated by 1 or 2 independently is substituted with a substituent selected from R ^B ; or Cy ^B is a 5 to 10-membered heteroaryl, one of the ring carbon atoms is substituted by a pendant oxygen group to form a carbonyl group and has 1, 2, 3 or 4 independently selected from Ring-forming heteroatoms of N, O and S; wherein N and S are optionally oxidized; wherein the 5 to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; Each R ^B is independently selected from C _1-6 alkyl, C _2-6 alkynyl, CN, halo, phenyl, 5 to 6 membered heteroaryl, C _3-7 cycloalkyl, 4 to 7 Member heterocycloalkyl, OR ^a2 , C(O)R ^b2 and C(O)NR ^c2 R ^d2 ; wherein the C _1-6 alkyl, C _2-6 alkynyl, phenyl, 5 to 6-membered heteroaryl group, C _3-7 cycloalkyl and 4 to 7 membered heterocycloalkyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is optionally substituted with 1, 2 , 3 or 4 phenylene groups substituted by substituents independently selected from R ^C ; each R ^C is independently selected from halo and C _1-4 alkyl; each R ¹¹ is independently OR ^a3 or C ( O)NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, C _1-6 alkyl, CN, phenyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H and C _1-6 alkyl; each R ^b1 is independently selected from C _1-6 alkyl; each R ^a3 , R ^c3 , R ^d3 and R ^a4 are independently selected from H and C _1-6 alkyl; and each R ^a2 , R ^b2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl, and phenyl; wherein each of the C _1-6 alkyl and phenyl is optionally separated by 1, 2, 3 or 4 Substituted with substituents independently selected from ^R12 .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C _1-6 alkyl, or (2) Wherein A ¹ is a bond, A ² is a bond or -C _1-3 alkylene-, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , NR ^c1 R ^d1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group of R ^A is passed through 1, 2, 3 or 4 substituted substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl, 6-membered heteroaryl or 4 to 7-membered heterocycle Alkyl; wherein each 6-membered heteroaryl and 4 to 7-membered heterocycloalkyl have at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S ; wherein N and S are optionally oxidized; wherein the ring carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with side oxy groups to form carbonyl groups; Cy ^B is C _3-10 Cycloalkyl or 4 to 10-membered heterocycloalkyl; wherein at least one ring carbon atom of C _3-10 cycloalkyl and 4 to 10-membered heterocycloalkyl is substituted with a pendant oxygen group to form a carbonyl group; wherein 4 to 10 The membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; and wherein C _3-10 cycloalkyl and 4 to 10 membered Each heterocycloalkyl group is optionally substituted with 1 or 2 substituents independently selected from R ^B ; or Cy ^B is a 5 to 10-membered heteroaryl group, one of the ring carbon atoms substituted with a pendant oxygen group to form a carbonyl group and Having 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein N and S are optionally oxidized; wherein the 5 to 10-membered heteroaryl group is optionally oxidized by 1, 2, 3 or 4 substituents independently selected from R ^B are further substituted; each R ^B is independently selected from C _1-6 alkyl, phenyl, OR ^a2 and C(O)NR ^c2 R ^d2 ; wherein the C _1-6 Alkyl and phenyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C Substituted phenylene; each R ^C is independently selected from halo and C _1-4 alkyl; each R ¹¹ is independently OR ^a3 ; each R ¹² is independently selected from halo, phenyl and OR ^a4 ; Each R ^a1 , R ^c1 and R ^d1 are independently selected from H and C _1-6 alkyl; each R ^b1 is independently selected from C _1-6 alkyl; each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl; and each R ^a2 , R ^c2 and R ^d2 are independently selected from H, C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl are each optional Substituted with 1, 2, 3 or 4 substituents independently selected from ^R12 .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 10-membered heterocycloalkyl group; wherein the 5- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heterocyclic atoms independently selected from N, O and S. atoms; wherein at least one ring-forming carbon atom of the 5- to 10-membered heterocycloalkyl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected from R ^B Substituted with a substituent; or Cy ^B is a 5 to 10-membered heteroaryl, one of its ring carbon atoms is substituted by a pendant oxygen group to form a carbonyl group and has 1, 2, 3 or 4 independently selected from N, O and S The ring-forming heteroatoms; wherein N and S are optionally oxidized; wherein the 5 to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; each R ^B independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl are optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is phenylene group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently halo; each R ¹¹ is independently OR ^a3 ; each R ¹² Independently selected from halo, phenyl and OR ^a4 ; Each R ^a1 , R ^c1 and R ^d1 are independently selected from H and C _1-6 alkyl; Each R ^b1 is independently selected from C _1-6 alkyl ; And each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein each of A ¹ , A ² and A ³ is a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 6-membered heteroaryl group in which one ring-forming carbon atom is substituted by a pendant oxygen group to form a carbonyl group and has 1 or 2 ring-forming heteroatoms independently selected from N, O and S; wherein N and S Optionally oxidized; wherein the 5- to 6-membered heteroaryl is optionally further substituted with 1 or 2 substituents independently selected from R ^B ; each R ^B is independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl groups are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is optionally substituted with 1, 2, 3 or 4 independently selected substituents. Phenylene substituted from the substituent of R ^C ; Each R ^C is independently halo; Each R ¹¹ is independently OR ^a3 ; Each R ¹² is independently selected from halo, phenyl and OR ^a4 ; Each R ^a1 , R ^c1 and R ^d1 are independently selected from H and C _1-6 alkyl; each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 10-membered heterocycloalkyl group; wherein the 5- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heterocyclic atoms independently selected from N, O and S. atoms; wherein at least one ring-forming carbon atom of the 5- to 10-membered heterocycloalkyl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected from R ^B Substituted with substituents; wherein each R ^B is independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl are optionally selected from 1, 2, 3 or 4 independently R ¹² is substituted with a substituent; Cy ^C is phenylene substituted with 1, 2, 3 or 4 substituents independently selected from R ^C as appropriate; each R ^C is independently halo; each R ¹¹ is independently OR ^a3 ; each R ¹² is independently selected from halo, phenyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H and C _1-6 alkyl; each R ^b1 are independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 10-membered heterocycloalkyl group; wherein the 5- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heterocyclic atoms independently selected from N, O and S. atoms; wherein at least one ring-forming carbon atom of the 5- to 10-membered heterocycloalkyl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected from R ^B Substituted with a substituent; or Cy ^B is a 5 to 10-membered heteroaryl, one of its ring carbon atoms is substituted by a pendant oxygen group to form a carbonyl group and has 1, 2, 3 or 4 independently selected from N, O and S The ring-forming heteroatoms; wherein N and S are optionally oxidized; wherein the 5 to 10-membered heteroaryl group is optionally further substituted with 1, 2, 3 or 4 substituents independently selected from R ^B ; each R ^B independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl are optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is phenylene group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently halo; each R ¹¹ is independently OR ^a3 ; each R ¹² are independently selected from halo, phenyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 are independently selected from H and C _1-6 alkyl; alternatively, R ^c1 and R ^d1 connected to the same N atom together with The N atoms to which it is attached together form a 6-membered heterocycloalkyl group; each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl. .

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 6-membered heteroaryl group in which one ring-forming carbon atom is substituted by a pendant oxygen group to form a carbonyl group and has 1 or 2 ring-forming heteroatoms independently selected from N, O and S; wherein N and S Optionally oxidized; wherein the 5- to 6-membered heteroaryl is optionally further substituted with 1 or 2 substituents independently selected from R ^B ; each R ^B is independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl groups are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is optionally substituted with 1, 2, 3 or 4 independently selected substituents. Phenylene substituted from the substituent of R ^C ; Each R ^C is independently halo; Each R ¹¹ is independently OR ^a3 ; Each R ¹² is independently selected from halo, phenyl and OR ^a4 ; Each R ^a1 , R ^c1 and R ^d1 are independently selected from H and C _1-6 alkyl; alternatively, R ^c1 and R ^d1 connected to the same N atom together with the N atom to which they are connected form a 6-membered heterocycloalkyl group ; Each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein each of A ¹ , A ² and A ³ is a bond and ^RA is C _1-6 alkyl, or (2) Each of A ¹ and A ² is a bond, A ³ is Cy ^A3 and R ^A is C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _1-6 alkyl group is optionally substituted by 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; R ² is H; R ³ is H; Cy ^A3 is C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups to form carbonyl; Cy ^B is a 5- to 10-membered heterocycloalkyl group; wherein the 5- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heterocyclic atoms independently selected from N, O and S. atoms; wherein at least one ring-forming carbon atom of the 5- to 10-membered heterocycloalkyl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heterocycloalkyl group is optionally substituted with 1 or 2 independently selected from R ^B Substituted with substituents; wherein each R ^B is independently selected from C _1-6 alkyl and phenyl; wherein the C _1-6 alkyl and phenyl are optionally selected from 1, 2, 3 or 4 independently R ¹² is substituted with a substituent; Cy ^C is phenylene substituted with 1, 2, 3 or 4 substituents independently selected from R ^C as appropriate; each R ^C is independently halo; each R ¹¹ is independently OR ^a3 ; each R ¹² is independently selected from halo, phenyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H and C _1-6 alkyl; alternatively, is connected to R ^c1 and R ^d1 of the same N atom together with the N atom to which they are connected form a 6-membered heterocycloalkyl group; each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected Selected from H and C _1-6 alkyl.

In some embodiments: R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and ^RA is C(O)NR ^c1 R ^d1 Or C _1-6 alkyl; or (2) wherein A ¹ is a bond, A ² is a bond or -C _1-3 alkyl-, A ³ is Cy ^A3 and R ^A is H, C _{1- 6Alkyl} , CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; wherein the C _{1- 6} The alkyl group is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; (3) wherein A ¹ is Cy ^A1 , A ² is Y, Y is C(O), and A ³ is Cy ^A3 and ^RA is H; or (4) where A ¹ is a bond, A ² is Cy ^A2 , A ³ is Cy ^A3 , where ^RA is C _1-6 alkyl; R ² is H; R ³ is H; Cy ^A3 is 5 to 6 membered heteroaryl, C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein 4 to 7 membered heterocycloalkyl has at least one ring carbon atom and 1, 2 , 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally substituted with pendant oxygen groups. Forming a carbonyl group; Cy ^B is a 5- to 10-membered heterocycloalkyl group; wherein the 5- to 10-membered heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3 or 4 independently selected from N, O and S Ring-forming heteroatoms; wherein at least one ring-forming carbon atom of the 5- to 10-membered heterocycloalkyl group is substituted with a pendant oxygen group to form a carbonyl group; and wherein the 5- to 10-membered heterocycloalkyl group is optionally substituted by 1 or 2 independently selected Substituted from the substituents of R ^B ; Each R ^B is independently selected from halo, CN, C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 5- to 6-membered heteroaryl , 4 to 7-membered heterocycloalkyl, phenyl, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , wherein the C _1-6 alkyl, C _2-6 alkynyl, C _{3 -6} cycloalkyl, 5 to 6 membered heteroaryl, 4 to 7 membered heterocycloalkyl and phenyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is phenylene group optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; each R ^C is independently halo; each R ¹¹ is independently OR ^a3 or C(O) NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, CN, C _1-6 alkyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H and C _1-6 alkyl ; Alternatively, R ^c1 and R ^d1 connected to the same N atom together with the N atom to which they are connected form a 6-membered heterocycloalkyl group; Each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 are independently selected from H and C _1-6 alkyl.

In some embodiments, Cy ^B is , , , ^CyB -1 ^CyB -2 ^CyB -3 , , or ^CyB -8 ^CyB -9 ^CyB -10 ^CyB -11 Among them, Cy ^B -1, Cy ^B -2, Cy ^B -3, Cy ^B -8, Cy ^B -9, Cy ^B -10, Cy ^B -4 and Cy ^B -11 each undergo 1, 2 or 3 as appropriate. Independently selected ^RB group substitution; R ¹ is A ¹ -A ² -A ^{3 -RA} , (1) wherein A ¹ , A ² and A ³ are each a bond and R ^A is C(O)NR ^c1 R ^d1 or C _1-6 alkyl; or (2) wherein A ¹ is a bond, A ² is a bond or -C _1-3 alkyl-, A ³ is Cy ^A3 and R ^A is H, C _1-6 alkyl, CN, OR ^a1 , C(O)R ^b1 , C(O)NR ^c1 R ^d1 , NR ^c1 R ^d1 , C(O)OR ^a1 or S(O) ₂ R ^b1 ; where C _1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹¹ ; (3) wherein A ¹ is Cy ^A1 , A ² is Y, and Y is C(O), A ³ is Cy ^A3 and R ^A is H; or (4) where A ¹ is a bond, A ² is Cy ^A2 , A ³ is Cy ^A3 , where R ^A is C _1-6 alkyl; R ² is H; R ³ is H; Cy ^A3 is 5 to 6 membered heteroaryl, C _3-7 cycloalkyl or 4 to 7 membered heterocycloalkyl; wherein the 4 to 7 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3 or 4 ring-forming heteroatoms independently selected from N, O and S; wherein the ring-forming carbon atoms of C _3-7 cycloalkyl and 4 to 7-membered heterocycloalkyl are optionally modified by pendant oxygen group substituted to form a carbonyl group; each R ^B is independently selected from halo, CN, C _1-6 alkyl, C _2-6 alkynyl, C _3-6 cycloalkyl, 5- to 6-membered heteroaryl, 4 to 7-membered heterocycloalkyl, phenyl, OR ^a2 , C(O)R ^b2 , C(O)NR ^c2 R ^d2 , wherein the C _1-6 alkyl, C _2-6 alkynyl, C _3-6 Cycloalkyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocycloalkyl and phenyl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from R ¹² ; Cy ^C is optional Phenylene group substituted with 1, 2, 3 or 4 substituents independently selected from R ^C ; Each R ^C is independently a halo group; Each R ¹¹ is independently OR ^a3 or C(O)NR ^c3 R ^d3 ; each R ¹² is independently selected from halo, CN, C _1-6 alkyl and OR ^a4 ; each R ^a1 , R ^c1 and R ^d1 is independently selected from H and C _1-6 alkyl; or , R ^c1 and R ^d1 connected to the same N atom together with the N atom to which they are connected form a 6-membered heterocycloalkyl group; each R ^b1 is independently selected from C _1-6 alkyl; and each R ^a3 and R ^a4 is independently selected from H and C _1-6 alkyl.

It is further to be understood that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided combined in a single embodiment. Conversely, various features of the invention, which are described for brevity in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

At various places in this specification, substituents of the compounds provided herein are disclosed in groups or ranges. It is specifically intended that the present invention include each and every individual subcombination of the members of such groups and ranges. For example, the term "C _1-6 alkyl" is particularly intended to reveal methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl, respectively.

In some places, these definitions or examples refer to specific rings (eg, azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings may be attached to any ring member with the proviso that the valence of the atom is not exceeded. For example, the azetidine ring can be attached at any position on the ring, and the azetidin-3-yl ring is attached at the 3-position.

The term "n-member" (where n is an integer) generally describes the number of ring-forming atoms in a portion with n number of ring-forming atoms. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring and 1,2,3,4-tetrakis Hydro-naphthalene is an example of a 10-membered cycloalkyl group.

For compounds provided herein in which one of the variables occurs more than once, each variable may be independently selected to define a different part of the population of variables. For example, when a structure is described as having two R groups present simultaneously on the same compound, the two R groups may represent different moieties independently selected from the group defined with respect to R. In another example, when optionally multiple substituents are represented by: It should be understood that the substituent R can appear p times on the ring, and R can be a different part each time it appears. It is understood that each R group can displace any hydrogen atom attached to a ring atom, including one or both of the ( _CH2 ) _n hydrogen atoms. Furthermore, in the above examples, if the variable Q is to be defined to include hydrogen, such as when Q is said to be _CH2 , NH, etc., any floating substituent (such as R in the above examples) may displace the hydrogen of the Q variable as well as the ring hydrogen in any other immutable component.

As used herein, the phrase "substituted, as appropriate" means unsubstituted or substituted. Substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent (eg, a pendant oxygen group) can displace two hydrogen atoms. It should be understood that substitution of a given atom is not limited by valence.

In these definitions, the term “C _nm ” means a range, inclusive, where n and m are integers and represent the number of carbons. Examples include C _1-4 , C _1-6 and the like.

As used herein, the term "C _nm alkyl" alone or in combination with other terms refers to a straight or branched chain saturated hydrocarbon radical having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher Carbon number homologs, such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and similar groups. In some embodiments, alkyl groups contain 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, "C _nm alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds and having n to m carbons. Examples of alkenyl groups include, but are not limited to, vinyl, n-propenyl, isopropenyl, n-butenyl, di-butenyl and the like. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, "C _nm alkynyl" refers to an alkyl group having one or more carbon-carbon bonds and having n to m carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term "C _nm alkylene", alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane -1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methyl-propane-1,3-diyl groups and similar groups. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

As used herein, the term "C _nm alkoxy", alone or in combination with other terms, refers to a group of the formula -O-alkyl, where the alkyl group has n to m carbons. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tert-butoxy). oxygen group) and similar groups. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamine (e.g., N-(n-propyl)amine and N-isopropylamine), N-butyl Amino groups (eg, N-(n-butyl)amine and N-(tert-butyl)amine) and the like.

As used herein, the term "C _nm alkoxycarbonyl" refers to a group of the formula -C(O)O-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl) Oxycarbonyl) and similar groups.

As used herein, the term "C _nm alkylcarbonyl" refers to a group of the formula -C(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl). (carbonyl) and similar groups.

As used herein, the term "C _nm alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfonamide" refers to a group of the formula -NHS(O) ₂ -alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "amidosulfonyl" refers to a group _of formula -S(O) _2NH2 .

As used herein, the term "C _nm alkylaminosulfonyl" refers to a group of the formula -S(O) _2NH (alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "di(C _nm alkyl)amine sulfonyl" refers to a group of the formula -S(O) ₂ N(alkyl) ₂ , where each alkyl group independently has n to m carbon atom. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "amidosulfonamide" refers to a group _of the formula -NHS(O) _2NH2 .

As used herein, the term "C _nm alkylaminosulfonylamine" refers to a group of the formula -NHS(O) _2NH (alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "di(C _nm alkyl)aminosulfonylamine" refers to a group of the formula -NHS(O) ₂ N(alkyl) ₂ , wherein each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "aminocarbonylamino" alone or in combination with other terms refers to a group of the formula -NHC(O) _NH .

As used herein, the term "C _nm alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "di(C _nm alkyl)aminocarbonylamino" refers to a group of the formula -NHC(O)N(alkyl) ₂ , where each alkyl group independently has n to m carbons atom. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylamine methyl" refers to a group of the formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "thio" refers to a group of formula -SH.

As used herein, the term "C _nm alkylthio" refers to a group of the formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm alkylsulfonyl" refers to a group of the formula -S(O) ₂ -alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "amine" refers to a group of formula _-NH .

As used herein, the term "carboxylic acid" refers to _a group of the formula -C(O)NH.

As used herein, the term "carbonyl", alone or in combination with other terms, refers to a -C(=O)- group, which may also be written as C(O).

As used herein, the term "carboxy" refers to the -C(O)OH group.

As used herein, the term "cyano-C _1-3 alkyl" refers to a group of the formula -(C _1-3 alkylene)-CN.

As used herein, the term "HO-C _1-3 alkyl" refers to a group of the formula -(C _1-3 alkylene)-OH.

As used herein, the term "HO-C1-3 alkyl" refers to a group of the formula -(C1-3 alkylene)-OH.

As used herein, the term "bis( _Cnm -alkyl)amine" refers to a group of formula -N(alkyl) ₂ , wherein the two alkyl groups each independently have n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "bis( _Cnm -alkyl)aminemethyl" refers to a group of the formula -C(O)N(alkyl) ₂ , in which the two alkyl groups independently have n to m carbon atom. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, "halo" refers to F, Cl, Br or I. In some embodiments, the halo group is F, Cl, or Br. In some embodiments, the halo group is F or Cl.

As used herein, "C _nm haloalkoxy" refers to a group of the formula -O-haloalkyl having n to m carbon atoms. An example of a haloalkoxy group is OCF ₃ . In some embodiments, haloalkoxy groups are only fluorinated. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term "C _nm haloalkyl", alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s + 1 halogen atoms which may be the same or different, where "s" is in the alkyl group The number of carbon atoms, where the alkyl group has n to m carbon atoms. In some embodiments, haloalkyl groups are only fluorinated. In some embodiments, alkyl groups have 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, "cycloalkyl" refers to non-aromatic cyclic hydrocarbons, including cyclic alkyl and/or alkenyl groups. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings) groups and heterocyclic rings. The ring carbon atoms of the cycloalkyl group may optionally be substituted with pendant oxygen groups or sulfide ion groups (such as C(O) or C(S)). Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the cycloalkyl ring, such as cyclopentane, cyclohexane, and the like. benzo or thienyl derivatives. The cycloalkyl group containing a fused aromatic ring can be connected through any ring-forming atom, including the ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9 or 10 ring carbons (C _3-10 ). In some embodiments, cycloalkyl is C _3-10 monocyclic or bicyclic cycloalkyl. In some embodiments, cycloalkyl is C _3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl group is a C _3-10 monocyclic or bicyclic non-aromatic carbocyclic ring, which optionally has ring members substituted with pendant oxygen groups (=O) or sulfion groups (=S) and optionally Cases have a phenyl group fused to the non-aromatic part of the ring structure or a 5 to 6 membered aromatic heterocycle, where the heterocycle has 1 to 3 ring members independently selected from N, S or O. In some embodiments, the cycloalkyl group is a C _3-7 monocyclic non-aromatic carbocyclic ring, which optionally has ring members substituted with pendant oxygen groups (=O) or sulfion groups (=S) and optionally has A phenyl group or a 5- to 6-membered aromatic heterocyclic ring fused to a non-aromatic part of the ring structure, wherein the heterocyclic ring has 1 to 3 ring members independently selected from N, S or O. In some embodiments, cycloalkyl is C _3-7 monocyclic cycloalkyl. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornane Norbornyl, norpinyl, norcarnyl and similar groups. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, the term "aryl", alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (eg, having 2, 3, or 4 fused rings). Examples of aryl rings include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and the like. In some embodiments, an aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, aryl groups are monocyclic or bicyclic groups. In some embodiments, aryl is phenyl or naphthyl. In some embodiments, aryl is phenyl.

As used herein, the term "phenylene" refers to a divalent phenyl linking group. In some embodiments, the phenylene group is optionally substituted as described herein.

As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from the group consisting of sulfur, oxygen, and nitrogen. In some embodiments, a heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N in the heteroaryl moiety can be an N-oxide. In one embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group is 5 to 6 membered heteroaryl. In certain embodiments, heteroaryl is a monocyclic or bicyclic aromatic ring system having 5 to 10 ring atoms, wherein 1 to 4 ring atoms are heteroatoms independently selected from N, O, and S, Among them, N and S as ring members are each optionally oxidized, and the carbocyclic ring members are optionally replaced with carbonyl groups. In another preferred embodiment, the heteroaryl group is a monocyclic aromatic ring system having 5 to 6 ring atoms, wherein 1 to 4 ring atoms are heteroatoms independently selected from N, O and S, Among them, N and S as ring members are each optionally oxidized, and the carbocyclic ring members are optionally replaced with carbonyl groups.

In some embodiments, heteroaryl is a five- or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl group having five ring atoms in the ring, one or more (eg, 1, 2, or 3) of the ring atoms being independently selected from N, O, and S. Exemplary five-membered ring heteroaryl groups are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, and 1,2,3-triazolyl , tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1, 2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl group having six ring atoms in the ring, one or more (eg, 1, 2, or 3) of the ring atoms being independently selected from N, O, and S. Exemplary six-membered ring heteroaryl groups are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, pyridone, uracil, and pyridazinyl. In some embodiments, the pyridones are substituted, such as 1-methylpyridin-2(1H)-one and 1-phenylpyridin-2(1H)-one. In some embodiments, uracil is substituted with phenyl, isopropyl, and pyridyl, for example. In some embodiments, uracil is substituted with phenyl and isopropyl, such as 1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine. In some embodiments, uracil is substituted with pyridyl and isopropyl, such as 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4 -Ectoine.

As used herein, the term "heteroaryl" refers to a divalent heteroaryl linking group. In some embodiments, heteroaryl groups are optionally substituted as described herein.

As used herein, "heterocycloalkyl" refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyl groups include monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Examples of heterocycloalkyl include pyrrolidin-2-one, 1,3-isoxazolidin-2-one, piperanyl, tetrahydropyranyl, oxybenzyl, azetidinyl, morpholinyl , thiomorpholinyl, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl base, imidazolidinyl, azepanyl, benzazapene and similar groups. The ring carbon atoms and heteroatoms of the heterocycloalkyl group may optionally be substituted by pendant oxygen groups or sulfide ion groups (for example, C(O), S(O), C(S) or S(O) ₂ , etc.). Heterocycloalkyl groups may be attached via ring carbon atoms or ring heteroatoms. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. The definition of heterocycloalkyl also includes moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond), such as benzo or thiophenes such as piperidine, morpholine, azole, etc. base derivatives. The heterocycloalkyl group containing a fused aromatic ring can be connected through any ring atom, including the ring atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a dihydropyran ring, a tetrahydropyran ring, a tetrahydropyridine, an azetidine ring, or Tetrahydrofuran ring. In certain embodiments, heterocycloalkyl is a monocyclic or bicyclic non-aromatic ring or ring system having 4 to 10 ring atoms, wherein 1 to 4 ring atoms are independently selected from N, O, and S Heteroatoms, in which N and S as ring members are each optionally oxidized, carbocyclic members are optionally replaced with carbonyl groups, and the heterocycloalkyl group is optionally fused with a 5- to 6-membered heteroaryl or phenyl ring, where A 5- to 6-membered heteroaryl ring may have 1 to 3 heteroatom ring members independently selected from N, S, and O. In another embodiment, heterocycloalkyl is a monocyclic non-aromatic ring or ring system having 4 to 6 ring atoms, wherein 1 to 2 ring atoms are independently selected from N, O, and S. Atoms in which N and S as ring members are each optionally oxidized, carbocyclic members are optionally replaced by carbonyl groups, and the heterocycloalkyl group is optionally fused with a 5- to 6-membered heteroaryl or phenyl ring, of which 5 to 6-membered heteroaryl or phenyl rings are optionally fused. A 6-membered heteroaryl ring may have 1 to 3 heteroatom ring members independently selected from N, S, and O. In some embodiments, the 10-membered heterocycloalkyl is 7,8-dihydroquinoline-2,5(1H,6H)-dione. In some embodiments, the 6-membered heterocycloalkyl is piperidinyl, piperazinyl, or tetrahydropyranyl.

In some embodiments, as used herein, aryl (eg, phenyl), heteroaryl, heterocycloalkyl, or cycloalkyl (eg, in the variables Cy ^A1 , Cy ^A2 , Cy ^A3 , Cy ^C , etc.) Can be a terminal group or an internal group (eg, a divalent linker). In some embodiments, the terms aryl, heteroaryl, heterocycloalkyl and cycloalkyl and their corresponding aryl, heteroaryl, heterocycloalkyl and cycloalkyl terms are used interchangeably. Those skilled in the art will readily appreciate that based on the structure, the substituents described herein and the context in which the term appears, this group is a terminal substituent or linker. For example, although the present disclosure may enumerate phenyl in the definition of variables such as Cy ^A2 , depending on the substitution pattern, the present disclosure also encompasses phenyl.

As used herein, "C _nm cycloalkyl-C _op alkylene" refers to a group of the formula - alkylene-cycloalkylene, wherein the cycloalkylene group has n to m ring members and the alkylene group has o to p carbon atoms.

As used herein, "C _{nmheterocycloalkyl} -C _op alkylene" refers to a group of the formula -alkylene-heterocycloalkylene, wherein heterocycloalkyl has n to m ring members and alkylene Has o to p carbon atoms.

As used herein, "phenyl-C _op alkylene" refers to a group of the formula -alkylene-phenyl, wherein the alkylene group has o to p carbon atoms.

As used herein, "C _nm aryl-C _op alkylene" refers to a group of the formula -alkylene-aryl, wherein aryl has n to m ring members and alkylene has o to p carbons atom.

As used herein, "C _nm heteroaryl-C _op alkylene" refers to a group of the formula -alkylene-heteroaryl, wherein the heteroaryl group has n to m ring members and the alkylene group has o to p carbon atoms.

As used herein, the term "pendant oxy" refers to an oxygen atom as a divalent substituent that when attached to a carbon forms a carbonyl group (e.g., C=O), or attached to a heteroatom to form a terine or terine group .

In some places, these definitions or examples refer to specific rings (eg, azetidine ring, pyridine ring, etc.). Unless otherwise indicated, these rings may be attached to any ring member with the proviso that the valence of the atom is not exceeded. For example, the azetidine ring can be attached at any position on the ring, while the pyridin-3-yl ring is attached at the 3-position.

The compounds described herein can be asymmetric (eg, have one or more stereocenters). Unless otherwise indicated, all stereoisomers, such as enantiomers and diastereomers, are contemplated. Compounds of the present disclosure containing asymmetrically substituted carbon atoms can be isolated into optically active or racemic forms. Methods are known in the art on how to prepare optically active forms from optically inactive starting materials, such as by resolution of racemic mixtures or by stereoselective synthesis. Various geometric isomers of alkenes, C=N double bonds, and the like may also exist in the compounds described herein, and all such stable isomers are encompassed by this disclosure. Cis and trans geometric isomers of the disclosed compounds are described and can be separated into mixtures of isomers or individual isomeric forms. In some embodiments, Compound (R) -Configuration. In some embodiments, the compound has the (S) -configuration.

Resolution of racemic mixtures of compounds can be accomplished by any of a variety of methods known in the art. One example method involves fractional recrystallization using a chiral resolving acid as an optically active salt-forming organic acid. Suitable resolving agents for the fractional recrystallization process are, for example, optically active acids such as tartaric acid in the D and L forms, diethyl tartaric acid, benzyl tartaric acid, mandelic acid, malic acid, lactic acid or various optically active acids. Camphorsulfonic acid, such as -camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereomerically pure forms of -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, Norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and their analogs.

The racemic mixture can also be resolved by elution on a column packed with an optically active resolving agent (eg, dinitrobenzylphenylglycine). Suitable dissolution solvent compositions can be determined by those skilled in the art.

Compounds provided herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond with an adjacent double bond along with concomitant migration of a proton. Tautomeric forms include proton transfer tautomers, which are isomeric protonation states with the same empirical formula and overall charge. Examples of proton transfer tautomers include keto-enol pairs, amide-amide acid pairs, lactam-lactam imine pairs, enamine-imine pairs, and those in which a proton may occupy a heterocyclic system. Cyclic forms with two or more positions, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H -Pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

All compounds and their pharmaceutically acceptable salts are found together with other substances such as water and solvents (eg, hydrates and solvates) or can be isolated.

In some embodiments, preparing a compound may involve adding an acid or base to effect, for example, the desired reaction or formation of a catalyzed salt form, such as an acid addition salt.

Examples of acids may be inorganic acids or organic acids, and include, but are not limited to, strong acids and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weak acids include, but are not limited to, acetic acid, propionic acid, butyric acid, benzoic acid, tartaric acid, valeric acid, caproic acid, heptanoic acid, caprylic acid, nonanoic acid, and capric acid.

Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate and sodium bicarbonate. Some examples of strong bases include, but are not limited to, hydroxides, alkoxides, metal amide, metal hydride, metal dialkyl amide, and arylamine; where alkoxides include methyl, ethyl, and Lithium, sodium and potassium salts of tributyl oxide; metal amide, including sodium amide, potassium amide and lithium amide; metal hydrides, including sodium hydride, potassium hydride and lithium hydride; and metal dialkyl amide Amines include lithium, sodium and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl and cyclohexyl substituted amide.

In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation may include, for example, enrichment of a composition provided herein. Substantially separating may include containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about A composition of 99% by weight of a compound provided herein or a salt thereof. Methods for isolating compounds and their salts are routine in the art.

The compounds of the present invention may also include all isotopes of atoms present in intermediates or final compounds. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the present invention may be replaced or substituted by naturally or non-naturally abundant atomic isotopes. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, compounds include two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for including isotopes in organic compounds are known in the art.

Substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements, and may therefore be preferable in certain circumstances. (A. Kerekes et al . J. Med. Chem. 2011 , 54 , 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015 , 58 , 308-312).

The term "compound" as used herein is intended to include all stereoisomers, geometric isomers, tautomers and isotopes of the stated structures. Unless otherwise indicated, compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms.

The phrase "pharmaceutically acceptable" is used herein to mean, within the scope of reasonable medical judgment, suitable for contact with human and animal tissue without undue toxicity, irritation, allergic reactions or other problems or complications, and with reasonable benefit. / Those compounds, substances, compositions and/or dosage forms with comparable risk ratios.

This application also includes pharmaceutically acceptable salts of the compounds described herein. The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acid or base moiety into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; basic or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts of the present disclosure include, for example, conventional nontoxic salts of the parent compound formed from nontoxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Generally, such salts may be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; typically, as Non-aqueous media such as diethyl ether, ethyl acetate, alcohols (for example, methanol, ethanol, isopropyl alcohol or butanol) or acetonitrile (ACN) are preferred. Lists of suitable salts can be found in Remington's Pharmaceutical Sciences , 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418 and Journal of Pharmaceutical Science , 66, 2 (1977), each of which is incorporated by reference in its entirety. into this article.

The following abbreviations may be used herein: AcOH (acetic acid); Ac ₂ O (acetic anhydride); aq. (aqueous solution); atm. (atmospheric pressure); Boc (tert-butoxycarbonyl); br (broad); Cbz (carboxybenzene) Methyl); calc. (calculated value); d (double peak); dd (double peak of double peak); DCM (dichloromethane); DEAD (diethyl azodicarboxylate); DIAD ( N , N' -Diisopropyl azidodicarboxylate); DIPEA ( N , N -diisopropylethylamine); DMF ( N , N -dimethylformamide); Et (ethyl); EtOAc (ethyl acetate) ester); g (grams); h (hours); HATU ( N , N , N' , N' -tetramethyl- O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate ); HCl (hydrochloric acid); HPLC (high performance liquid chromatography); Hz (hertz); J (coupling field number); LCMS (liquid chromatography-mass spectrometry); m (multiplet); M (mol) ; m CPBA (3-chloroperoxybenzoic acid); MgSO ₄ (magnesium sulfate); MS (mass spectrometry); Me (methyl); MeCN (acetonitrile); MeOH (methanol); mg (milligram); min. (minutes); mL (milliliters); mmol (millimoles); N (standard); NaHCO ₃ (sodium bicarbonate); NaOH (sodium hydroxide); Na ₂ SO ₄ (sodium sulfate); NH ₄ Cl (chlorine ammonium hydroxide); NH ₄ OH (ammonium hydroxide); nM (naimole); NMR (nuclear magnetic resonance spectroscopy); OTf (triflate); Pd (palladium); Ph (phenyl); pM (picomole); PMB (p-methoxybenzyl), POCl ₃ (phosphonium chloride); RP-HPLC (reverse phase high performance liquid chromatography); s (singlet peak); t (triplet peak) or tertiary); TBS (tertiary butyldimethylsilyl); tert (tertiary); tt (triplet of triplet); t -Bu (tertiary butyl); TFA (trifluoroacetic acid); THF (Tetrahydrofuran); µg (micrograms); µL (microliters); µM (micromoles); wt% (weight percentage).

As used herein, the term "cell" is intended to refer to cells in vitro, ex vivo, or in vivo. In some embodiments, the ex vivo cells may be part of a tissue sample excised from an organism, such as a mammal. In some embodiments, the in vitro cells may be cells in cell culture. In some embodiments, in vivo cells are cells viable in an organism such as a mammal.

As used herein, the term "contacting" means bringing the designated moieties together in an in vitro system or an in vivo system. For example, "contacting" a TAM kinase with a compound of the disclosure includes administering a compound of the disclosure to an individual or patient (such as a human) with TAM and, for example, introducing a compound of the disclosure into a cell or purified preparation containing a TAM kinase. in the sample.

As used herein, the terms "individual" or "patient" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, Horse or primate, preferably human.

As used herein, the phrase "therapeutically effective amount" means an amount of an active compound or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal, individual or human being sought by a researcher, veterinarian, physician or other clinician. quantity.

As used herein, the term "treating" or "treatment" means 1) inhibiting a disease; e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting pathology or symptoms of the disease, condition, or disorder (also i.e., preventing the further development of pathology and/or symptoms) or 2) alleviating disease; for example, alleviating a disease, condition or disorder in an individual who is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder (i.e., causing pathology and/or Symptom reversal).

As used herein, the terms "preventing" or "prevention" refer to preventing a disease; for example, preventing a disease, condition, or disorder in an individual who is predisposed to the disease, condition, or disorder but who has not yet experienced or exhibited the pathology or symptoms of the disease. . synthesis

The compounds provided herein, including salts thereof, can be prepared using known organic synthesis techniques and according to various possible synthetic routes.

Reactions used to prepare the compounds provided herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. A suitable solvent may be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, one skilled in the art can select a suitable solvent for the particular reaction step.

Preparation of the compounds provided herein may involve protection and deprotection of various chemical groups. The requirements for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. Protective group chemistry can be found, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

The reaction can be monitored according to any suitable method known in the art. For example, by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g. UV-visible) or mass spectrometry) or by chromatography such as High performance liquid chromatography (HPLC) or thin layer chromatography) to monitor product formation.

As used herein, the expressions "ambient temperature," "room temperature," and "r.t." are as understood in the art and generally refer to a temperature such as the reaction temperature, that is, about the temperature of the room in which the reaction is conducted. Temperature, for example, a temperature of about 20°C to about 30°C.

The compounds as disclosed herein can be prepared by those skilled in the art according to preparation routes known in the literature and according to various possible synthetic routes. Examples of synthetic methods for preparing compounds of this application are provided below in Scheme 1.

Reactions used to prepare the compounds provided herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. A suitable solvent may be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out, for example, at a temperature ranging from the freezing temperature of the solvent to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, one skilled in the art can select a suitable solvent for the particular reaction step.

Preparation of the compounds provided herein may involve protection and deprotection of various chemical groups. The requirements for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. Protective group chemistry can be found, for example, in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis , 3rd ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

The reaction can be monitored according to any suitable method known in the art. For example, by spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g. ¹ H or ¹³ C), infrared spectroscopy, spectrophotometry (e.g. UV-visible) or mass spectrometry) or by chromatography such as High performance liquid chromatography (HPLC) or thin layer chromatography) to monitor product formation.

As used herein, the expressions "ambient temperature," "room temperature," and "r.t." are as understood in the art and generally refer to a temperature such as the reaction temperature, that is, about the temperature of the room in which the reaction is conducted. Temperature, for example, a temperature of about 20°C to about 30°C.

Compounds as disclosed herein can be prepared by one skilled in the art according to preparation routes known in the literature. Compounds of formula I can be prepared according to Scheme 1. Compound (i) can be prepared by standard Suzuki coupling of bromide (ia) with boronic acid ester or acid (ib), where ^R1 contains alkenyl functionality. Catalytic hydrogenation of the R ¹ functionality using Pd on carbon or another suitable catalyst can subsequently provide compound (ii), wherein R ¹ contains an alkylene functionality. Selective treatment of compound (ii), for example using NBS, yields bromide (iii), which is subsequently treated directly with a boronic acid ester or acid (iv), for example under standard Suzuki coupling conditions, to yield compounds of formula I. Alternatively, compounds of formula I may be prepared via Suzuki coupling of bromide (iii) with boronic acid ester or acid (v) followed by reaction of the resulting amine (vi) with carboxylic acid (vii) and a suitable coupling reagent such as HATU or BOP . Process 1

The invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily appreciate that various non-critical parameters can be changed or modified to produce essentially the same results. As described below, the compounds of these examples were found to be inhibitors of TAM kinases.

Some of the compounds prepared were subjected to preparative LC-MS purification on a Waters mass-directed fractionation system. The basic equipment setup, experimental protocols, and control software used to operate these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem ., 4, 295 ( 2002 ); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem ., 5, 670 ( 2003 ); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem ., 6, 874-883 ( 2004 ). Isolated compounds are typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity checks under the following conditions: Instrument; Agilent 1100 Series, LC/MSD, Column: Waters Sunfire ^TM C ₁₈ 5 µm particle size, 2.1 ×5.0 mm, buffer: mobile phase A: 0.025% TFA in water, and mobile phase B: acetonitrile; gradient 2% to 80% B, within 3 minutes, flow rate is 2.0 mL/min.

As also shown in the Examples, some of the compounds prepared were separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detector. Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: pH = 2 purification: Waters Sunfire ^TM C ₁₈ 5 µm particle size, 19×100 mm column, with mobile phase A: 0.1 in water % TFA (trifluoroacetic acid) and mobile phase B: acetonitrile for elution; the flow rate was 30 mL/min and the separation gradient was run for each compound using a compound-specific method optimization protocol as described in the literature. Optimization [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6 , 874-883 (2004)]. The flow rate for a 30×100 mm column is typically 60 mL/min. pH _{= 10} purification: Waters The separation gradient was optimized for each compound using a compound-specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6 , 874-883 (2004)]. The flow rate for a 30×100 mm column is typically 60 mL/min. TAM kinase

Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus to regulate cellular events such as survival, growth, proliferation, differentiation, adhesion and migration. All RTKs contain extracellular ligand-binding domains and cytoplasmic protein tyrosine kinase domains. Ligand binding results in RTK dimerization, which induces cytoplasmic kinase activation and inhibits downstream signaling pathways. RTKs can be classified into different subfamilies based on their sequence similarities. The TAM subfamily consists of three RTKs, including TYRO3, AXL and MER (Graham et al., 2014, Nature reviews Cancer 14 , 769-785; and Linger et al., 2008, Oncogene 32 , 3420-3431). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands have been recognized for TAM kinases, growth arrest specific 6 (GAS6) and protein S (ProS). GAS6 can bind to and activate all three TAM kinases, and ProS is a ligand for MER and TYRO3 (Graham et al., 2014, Nature reviews Cancer 14 , 769-785).

TAM kinases are overexpressed in many cancers and have important roles in tumor initiation and maintenance; therefore, TAM inhibition represents a compelling way to target another class of oncogenic RTKs (Graham et al., 2014, Nature reviews Cancer 14 , 769-785; and Linger et al., 2008, Oncogene 32 , 3420-3431).

Axl was originally identified as a transforming gene in DNA from patients with chronic myelogenous leukemia (O'Bryan et al., 1991, Molecular and cellular biology 11, 5016-5031). GAS6 binds to Axl and induces subsequent autophosphorylation and activation of Axl tyrosine kinase. Axl activates several downstream signal transduction pathways, including PI3K-Akt, Raf-MAPK, and PLC-PKC (Feneyrolles et al., 2014, Molecular cancer therapeutics 13, 2141-2148; Linger et al., 2008, Oncogene 32, 3420-3431 ). AXL is overexpressed or amplified in a variety of malignant diseases, including lung, prostate, colon, breast, melanoma, and renal cell carcinoma (Linger et al., 2008, Oncogene 32 , 3420-3431). Excessive expression of AXL is associated with poor prognosis (Linger et al., 2008, Oncogene 32 , 3420-3431). Therefore, AXL activation promotes cancer cell survival, proliferation, angiogenesis, cancer metastasis, and resistance to chemotherapy and targeted therapy. AXL knockout or AXL antibodies can inhibit breast cancer and NSCLC cancer metastasis in vitro and block tumor growth in xenograft tumor models (Li et al., 2009, Oncogene 28 , 3442-3455). In pancreatic cancer cells, inhibition of AXL reduces cell proliferation and survival (Koorstra et al., 2009, Cancer biology & therapy 8 , 618-626). In prostate cancer, AXL inhibition reduces cell migration, invasion and proliferation (Tai et al., 2008, Oncogene 27 , 4044-4055). In addition, AXL overexpression or amplification is the main mechanism of resistance of lung cancer cells to EGFR inhibitors, and AXL inhibition can reverse this resistance (Zhang et al., 2012, Nature genetics 44 , 852-860).

Mer was originally identified as a phosphorylated protein from a lymphoblastoid expression library (Graham et al., 1995, Oncogene 10, 2349-2359). GAS6 and ProS can bind to Mer and induce phosphorylation and activation of Mer kinase (Lew et al., 2014. eLife, 3:e03385). Like Axl, Mer activation also transmits downstream signaling pathways, including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Oncogene 32, 3420-3431). MER is overrepresented in a variety of cancers, including multiple myeloma, gastric cancer, prostate cancer, breast cancer, melanoma, and rhabdomyosarcoma (Linger et al., 2008, Oncogene 32 , 3420-3431). MER knockdown inhibits the growth of multiple myeloma cells in vitro and in xenograft models (Waizenegger et al., 2014, Leukemia, 1-9). In acute myeloid leukemia, MER knockout induces apoptosis, reduces colony formation, and increases survival in mouse models (Lee-Sherick et al., 2013, Oncogene 32 , 5359-5368). MER inhibition increases apoptosis, reduces colony formation, increases chemosensitivity and reduces tumor growth in NSCLC (Linger et al., 2013, Oncogene 32 , 3420-3431). Similar effects were observed for MER knockout in melanoma (Schlegel et al., 2013) and glioblastoma (Wang et al., 2013, Oncogene 32 , 872-882).

Tyro3 was originally identified through PCR-based cloning studies (Lai and Lemke, 1991, Neuron 6, 691-704). Two ligands, GAS6 and ProS, can bind to and activate Tyro3. TYRO3 also plays a role in cancer growth and proliferation. TYRO3 is overexpressed in melanoma cells and knocking out TYRO3 induces apoptosis in these cells (Demarest et al., 2013, Biochemistry 52 , 3102-3118).

In addition to its role as a transforming oncogene, TAM kinases have emerged as potential immuno-oncology targets. The durable clinical responses to immune checkpoint blockade observed in cancer patients clearly demonstrate the important role of the immune system in tumor initiation and maintenance. Gene mutations from cancer cells can provide diverse antigens that immune cells can use to distinguish tumor cells from their normal counterparts. However, cancer cells have developed multiple mechanisms to evade host immune surveillance. In fact, one of the hallmarks of human cancer is its ability to avoid immune destruction. Cancer cells can induce an immunosuppressive microenvironment by promoting the formation of M2 tumor-associated macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells. Cancer cells can also produce high levels of immune checkpoint proteins (such as PD-L1) to induce T cell anergy or exhaustion. It is now clear that tumors designate certain immune checkpoint pathways as primary mechanisms of immune resistance (Pardoll, 2012, Cancer 12 , 252-264). These negative regulators, which use antibodies to antagonize T cell function, have demonstrated significant efficacy in clinical trials of a variety of malignant diseases, including advanced melanoma, non-small cell lung cancer and bladder cancer. Although these treatments have shown promising results, not all patients develop antitumor responses, suggesting that other immunosuppressive pathways are also important.

TAM kinases have been shown to function as checkpoints for immune activation in the tumor environment. All TAM kinases are expressed in NK cells, and TAM kinases inhibit the anti-tumor activity of NK cells. LDC1267, a small molecule TAM inhibitor, activates NK cells and blocks cancer metastasis in tumor models with different histologies (Paolino et al., 2014, Nature 507 , 508-512). Additionally, MER kinase contributes to the activity of tumor-associated macrophages by increasing the secretion of immunosuppressive cytokines, such as IL10 and IL4, and reducing the production of immune-activating cytokines, such as IL12 (Cook et al., 2013, The Journal of clinical investigation 123, 3231-3242). MER inhibition has been shown to reverse this effect. Therefore, MER knockout mice are resistant to PyVmT tumor formation (Cook et al., 2013, The Journal of clinical investigation 123 , 3231-3242). The role of TAM kinases in immune responses is also supported by studies in knockout mice. TAM triple knockout mouse (TKO) lines are viable. However, these mice exhibit signs of autoimmune disease, including enlarged spleen and lymph nodes, production of autoantibodies, swelling of footpads and joints, skin lesions, and systemic lupus erythematosus (Lu and Lemke, 2001, Science 293 , 306- 311). This is consistent with the knockout phenotype of recognized immuno-oncology targets such as CTLA4 and PD-1. Both CTLA-4 and PD-1 knockout mice display signs of autoimmune disease, and these mice die within weeks of birth (Chambers et al., 1997, Immunity 7 , 885-895; and Nishimura et al., 2001, Science 291 , 319-322).

TAM inhibition will not only have direct activity against neoplastic cells, but also activate anti-cancer immune responses. TAM inhibitors therefore represent a compelling approach as single agents for the treatment of cancer. In addition, TAM inhibitors can be combined with other targeted therapies, chemotherapy, radiation or immunotherapeutic agents to achieve maximum efficacy in the clinic. Instructions

Compounds of the present disclosure can modulate or inhibit the activity of TAM kinase. For example, a compound of the present disclosure can be used to inhibit the activity of a TAM kinase in a cell, individual, or patient in need of kinase inhibition by administering an inhibitory amount of a compound of the present disclosure to the cell, individual, or patient in need of kinase inhibition.

In some embodiments, compounds of the present disclosure are more selective for TAM kinases than for one or more other kinases. In some embodiments, compounds of the present disclosure are more selective for TAM kinases than other kinases. In some embodiments, the selectivity is 2 times or more, 3 times or more, 5 times or more, 10 times or more, 25 times or more, 50 times or more Or 100 times or more.

The compounds of the present invention can inhibit one or more of AXL, MER and TYRO3. In some embodiments, the compound is more selective for one TAM kinase than another TAM kinase. "Selective" means that the compound binds to or inhibits a TAM kinase with greater affinity or potency, respectively, compared to a reference enzyme, such as another TAM kinase. For example, a compound is more selective for AXL than MER and TYRO3, more selective for MER than AXL and TYRO3, or more selective for AXL and MER than TYRO3. In some embodiments, compounds inhibit all TAM family members (eg, AXL, MER, and TYRO3). In some embodiments, compounds are more selective for AXL and MER than for TYRO3 and other kinases. In some embodiments, provided herein is a method for inhibiting AXL and MER kinases, comprising contacting AXL and MER kinases with a compound provided herein, or a pharmaceutically acceptable salt thereof.

As TAM kinase inhibitors, the compounds of the present disclosure are suitable for the treatment of various diseases related to abnormal performance or activity of TAM kinases. Compounds that inhibit TAM kinases would be useful in providing a means of preventing tumor growth or inducing apoptosis in tumors, particularly by inhibiting angiogenesis. It is therefore expected that these compounds will prove useful in the treatment or prevention of proliferative disorders, such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or tumors with upregulation of receptor tyrosine kinases may be particularly sensitive to inhibitors.

In certain embodiments, the present disclosure provides a method of treating a disease or disorder mediated by a TAM kinase in a patient in need thereof, comprising administering to the patient a compound provided herein, or a pharmaceutically acceptable version thereof. Composition Steps.

For example, compounds of the present disclosure are useful in treating cancer. Examples of cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancer (e.g., laryngeal cancer, hypopharynx cancer cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and oral cavity cancer), kidney cancer, liver cancer (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, small cell lung cancer, cell carcinoma and non-small cell carcinoma, bronchial carcinoma, bronchial adenocarcinoma, pleuropulmonary blastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic visceral cancer), stomach cancer, thyroid cancer, parathyroid cancer, skin cancer (e.g., squamous cell carcinoma, Kaposi sarcoma, Merkel cell skin cancer), and Brain cancer (eg, astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal gland tumor).

Other cancers treatable by compounds disclosed herein include bone cancer, intraocular tumors, gynecological cancer, endocrine cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pituitary cancer, triple negative breast cancer (TNBC), and environmentally induced cancers. cancers (including those caused by asbestos).

Other examples of cancer include hematopoietic malignancies (such as leukemia or lymphoma), multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodge's Hodgkin's lymphoma or non-Hodgkin's lymphoma, myeloproliferative neoplasms (eg, polycythemia vera, essential thrombocythemia, and primary myelofibrosis) , Waldenstrom's Macroglubulinemia, pilocytic lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma and Burkitt's lymphoma.

Other cancers treatable by compounds disclosed herein include eye tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma and osteosarcoma.

The compounds of the present disclosure may also be suitable for inhibiting tumor metastasis.

In some embodiments, diseases and indications treatable with compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, neurological cancers, gynecological cancers, Cancer and skin cancer.

Exemplary blood cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), acute promyeloid leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin lymphoma (including relapsed or refractory NHL), follicular lymphoma (FL), Hodgkin lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenstrom's macroglobulinemia, pilocytic lymphoma, chronic myeloid lymphoma and Burch's lymphoma.

Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyosarcoma, rhabdomyosarcoma, fibromas, lipomas, hamartomas and malformations. fetal tumor.

Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (branchial tracheal) carcinoma, bronchial adenocarcinoma , enchondromatous hamartoma and mesothelioma.

Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, isletoma, glucagon gastrinoma, carcinoid tumor, vasoactive intestinal peptide tumor), small bowel cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma), leiomyoma, hemangioma, lipoma , neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colorectal cancer and cholangiocarcinoma.

Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilm's tumor [nephroblastoma], renal cell carcinoma), bladder cancer, and urinary tract cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma carcinoma, urothelial carcinoma), prostate cancer (adenocarcinoma, sarcoma) and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma , fibroadenomas, tumor-like tumors, lipomas).

Exemplary liver cancers include liver tumors (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

Exemplary bone cancers include, for example, osteosarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor of the notochord tumors, osteochondromas (osteochondral exostoses), benign enchondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors.

Exemplary neurological cancers include skull cancers (osteomas, hemangiomas, granulomas, xanthomas, osteitis deformans), meningeal cancers (meningiomas, meningiosarcomas, gliomatosis), brain cancers (astrocytoma, Medulloblastoma, glioma, ependymoma, blastoma (pineal tumor), glioblastoma, glioblastoma multiforme, oligodendritic glioblastoma, Schwannoma, retinoblastoma, congenital tumors) and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma) as well as neuroblastoma, Lhermitte-Duclos disease ), central nervous system (CNS) neoplasms, primary CNS lymphomas and spinal cord axis tumors.

Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, early neoplastic cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, intraepithelial carcinoma, Adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma)) and fallopian tube cancer (carcinoma).

Exemplary skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, moles dysplastic nevi, lipoma, hemangioma, dermatofibroma, and Keloid.

Exemplary head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cavity cancer, laryngeal cancer, nasopharyngeal cancer, paranasal sinus cancer, thyroid cancer, and parathyroid cancer cancer.

In some embodiments, the invention provides a method of treating hepatocellular carcinoma in a patient in need thereof, comprising the steps of: administering to the patient a compound of formula (I) or a compound as disclosed herein or a pharmaceutical agent thereof. Acceptable salts, or compositions containing compounds of formula (I) or as disclosed herein.

In some embodiments, the invention provides a method of treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head and neck cancer in a patient in need thereof, comprising the steps of: administering to the patient a compound of formula (I) or as disclosed herein A compound or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a compound as disclosed herein.

In some embodiments, the invention provides a method of treating cancer, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, Testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer and rhabdomyosarcoma.

Targeting TAM receptor tyrosine kinase may provide a therapeutic approach to treat viral diseases (T Shibata et al. The Journal of Immunology , 2014 , 192 , 3569-3581). The present invention provides a method of treating infections, such as viral infections. The method includes administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I) or any formula as described herein, a compound as cited in the patent claims of any application and described herein, or a salt thereof. Examples of viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D virus, adenovirus, poxvirus, simplex virus, Herpes virus, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, Marburg virus and measles virus. In some embodiments, viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, hepatitis (A, B, or C), herpes viruses (e.g., VZV, HSV-1, HAV-6, HSV- II and CMV, Epstein Barr virus), adenovirus, influenza virus, flavivirus (such as: West Nile, dengue, tick-borne encephalitis, yellow fever, Zika, echovirus, rhinovirus, coxsackie virus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, Parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.

In some embodiments, the invention provides a method of treating thrombosis (JMEM Cosemans et al. J. of Thrombosis and Haemostasis 2010 , 8 , 1797-1808 and A. Angelillo-Scherrer et al. J. Clin. Invest. 2008 , 118 , 583-596). Combination treatment

One or more other pharmaceutical agents or treatments, such as antiviral agents, chemotherapeutic or other anticancer agents, immune enhancers, immunosuppressive agents, radiation, antitumor and antiviral vaccines, cytokine therapy (e.g., IL2, GM -CSF, etc.) and/or tyrosine kinase inhibitors, may be used in combination with compounds of formula (I) or compounds as described herein to treat TAM-related diseases, disorders or conditions. These agents can be combined with the compounds of the invention in a single dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.

Suitable antiviral agents contemplated for use in combination with the compounds of the present disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors and other antiviral drugs .

Examples of suitable NRTIs include zidovudine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir dipivoxil [bi(POM)-PMEA]; lobucavir (BMS-180194) ); BCH-10652; emtricitabine [(-)-FTC]; β-L-FD4 (also known as β-L-D4C and named β-L-2',3'-dideoxy (dicleoxy-5-fluoro-cytidene); DAPD ((-)-β-D-2,6-diamino-purinedioxolane); and lodenosine (FddA ). Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine (BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG- 1549; MKC-442 (1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione ); and (+)-calanolide A (NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT) -538); indinavir (MK-639); nelfnavir (AG-1343); amrenavir (141W94); lasinavir (BMS) -234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafusil (pentafuside) and Yissum Project No. 11607.

Suitable agents for treating cancer in combination with the compounds of this application include chemotherapeutic agents, targeted cancer therapies, immunotherapy, or radiation therapy. The compounds of this application can be effectively used in combination with antihormonal agents to treat breast cancer and other tumors. Suitable examples are anti-estrogens (including but not limited to tamoxifen and toremifene), aromatase inhibitors (including but not limited to letrozole, alfa) anastrozole and exemestane), adrenocortical steroids (such as prednisone), progestins (such as megestrol acetate), and estrogen receptor antagonists ( For example, fulvestrant). Suitable antihormonal agents for the treatment of prostate cancer and other cancers may also be combined with the compounds of the present disclosure. Such antihormonal agents include antiandrogens (including (but not limited to) flutamide, bicalutamide, and nilutamide), luteinizing hormone-releasing hormone (LHRH) analogs (including leuprolide, oserelin, triptorelin and histrelin), LHRH antagonists (such as degarelix), androgen receptor Blockers (eg, enzalutamide) and agents that inhibit androgen production (eg, abiraterone).

Particularly for patients who have developed primary or acquired resistance to targeted therapies, compounds of the present disclosure may be used in combination with other agents or sequentially to antagonize membrane receptor kinases. Such therapeutic agents include those targeting EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, PDGFR, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, TrkC, ROS, c-Kit or Flt-3 and those targeting cancer-related fusions Inhibitors or antibodies to protein kinases such as Bcr-Abl and EML4-Alk. Inhibitors targeting EGFR include gefitinib and erlotinib, and inhibitors targeting EGFR/Her2 include (but are not limited to) dacomitinib, afatinib ), lapitinib and neratinib. Antibodies directed against EGFR include, but are not limited to, cetuximab, panitumumab, and necitumumab. Inhibitors of c-Met can be used in combination with TAM inhibitors. Such inhibitors include onartumzumab, tivantinib and INC-280. Agents targeting FGFR include (but are not limited to) AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493 and Debio1347. Agents targeting Trks include (but are not limited to) LOXO-101 and RXDX-101. Agents that target Abl (or Bcr-Abl) include imatinib, dasatinib, nilotinib, and ponatinib, and those that target Alk (or EML4-ALK ) include crizotinib.

Combining angiogenesis inhibitors with TAM inhibitors can be effective in certain tumors. Such angiogenesis inhibitors include antibodies directed against VEGF or VEGFR or kinase inhibitors of VEGFR. Antibodies or other therapeutic proteins directed against VEGF include bevacizumab and aflibercept. VEGFR kinase inhibitors and other anti-angiogenesis inhibitors include (but are not limited to) sunitinib, sorafenib, axitinib, cediranib, Pazopanib, regorafenib, brivanib and vandetanib.

Activation of intracellular signaling pathways is common in cancer, and agents that target components of these pathways are combined with receptor-targeting agents to enhance efficacy and reduce resistance. Examples of agents that may be combined with compounds of the present disclosure include PI3K-AKT-mTOR pathway inhibitors, Raf-MAPK pathway inhibitors, JAK-STAT pathway inhibitors, Pim kinase inhibitors, and inhibitors of protein chaperones and cell cycle progression.

Agents targeting PI3 kinase include, but are not limited to, pilaralisib, idelalisib, buparlisib, and IPI-549. In some embodiments, the PI3K inhibitor is selective for PI3K alpha, PI3K beta, PI3K gamma, or PI3K delta. mTOR inhibitors such as rapamycin, sirolimus, temsirolimus and everolimus can be combined with TAM kinase inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors) and trametinib, selumetinib and GDC-0973 ( MEK inhibitors). One or more inhibitors of JAK (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin Dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) also Can be combined with the compounds of this disclosure. In some embodiments, the JAK inhibitor is more selective for JAK1 than for JAK2 and JAK3. Agents targeting Pim kinase include, but are not limited to, LGH447, INCB053914, and SGI-1776.

Other suitable agents for use in combination with the compounds of the present disclosure include chemotherapy combinations, such as platinum-based pairs used in lung cancer and other solid tumors (cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus gemcitabine; cisplatin or carboplatin plus gemcitabine); European paclitaxel (docetaxel); cisplatin or carboplatin plus paclitaxel (paclitaxel); cisplatin or carboplatin plus pemetrexed (pemetrexed)) or gemcitabine plus paclitaxel-conjugated particles (Abraxane®).

Suitable chemotherapeutic or other anti-cancer agents include, for example, alkylating agents (including, but not limited to, nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), Such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan ^TM ), ifosfamide (ifosfamide), melphalan (melphalan), chlorambucil (chlorambucil), piperobromide (pipobroman), triethyl-melamine, triethylthiophosphonamide, busulfan, carmustine, lomustine, streptozotocin ( streptozocin, dacarbazine and temozolomide.

Other suitable agents for use in combination with compounds of the present disclosure include: dacarbazine (DTIC), optionally with other chemotherapy drugs such as carmustine (BCNU) and cisplatin; DTIC, BCNU, cisplatin, and The "Dartmouth regimen" consisting of tamoxifen; the combination of cisplatin, vinblastine (vinblastine) and DTIC; or temozolomide. The compounds provided herein may also be combined with immunotherapy drugs, including cytokines such as interferon alpha, interleukin 2, and tumor necrosis factor (TNF) inhibitors.

Suitable chemotherapeutic or other anti-cancer agents include, for example, antimetabolites (including, but not limited to, folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, fluuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine and gemcitabine.

Suitable chemotherapeutic or other anti-cancer agents further include, for example, certain natural products and their derivatives (eg, vinca alkaloids, anti-tumor antibiotics, enzymes, lymphokine and epipodophyllotoxin), such as vinblastine, vincristine, Vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin ), ara-C, paclitaxel (TAXOL ^TM ), mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide and teniposide.

Other cytotoxic agents include navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, and cyclophosphamide , ifosamide and droloxafine.

Also suitable are cytotoxic agents such as epipodophyllotoxin; antineoplastic enzymes; topoisomerase inhibitors; procarbazine; mitoxantrone; platinum coordination complexes such as cis Platinum and carboplatin); biological response modifiers; growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur and hematopoietic growth factors.

Other anti-cancer agents include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4, 4-1BB, and PD-1, or antibodies to cytokines (IL-10 , TGF-β, etc.).

Other anticancer agents include CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-CS4, RG7155, etc.).

Other anticancer agents include BET inhibitors (INCB054329, OTX015, CPI-0610, etc.), LSD1 inhibitors (GSK2979552, INCB059872, etc.), HDAC inhibitors (panobinostat, vorinostat, etc.) , DNA methyltransferase inhibitors (azacitidine and decitabine) and other epigenetic regulators.

Other anticancer agents include the Bcl2 inhibitor ABT-199 and other Bcl-2 family protein inhibitors.

Other anti-cancer agents include TGF beta receptor kinase inhibitors such as LY2157299.

Other anti-cancer agents include BTK inhibitors such as ibrutinib.

Other anticancer agents include beta-catenin pathway inhibitors, notch pathway inhibitors, and hedgehog pathway inhibitors.

Other anticancer agents include inhibitors of kinase-related cell proliferative disorders. Such kinases include (but are not limited to) Aurora-A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinase, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk and SGK.

Other anti-cancer agents also include those that block immune cell migration, such as antagonists of chemokine receptors, including CCR2 and CCR4.

Other anti-cancer agents also include those that augment the immune system, such as adjuvants or adoptive T cell transfer.

Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines and recombinant viruses.

One or more other immune checkpoint inhibitors can be used in combination with compounds as described herein to treat TAM-related diseases, disorders or conditions. Exemplary immune checkpoint inhibitors include inhibitors directed against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, spermine Acidase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1 and PD -L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA Point molecule. In some embodiments, compounds provided herein can be used in combination with one or more agents selected from the group consisting of KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001 or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN01876, or MK-1248.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CD20, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

Compounds of the present disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or TGFβ receptor.

Compounds of the present disclosure may be used in combination with one or more pharmaceutical agents to treat diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).

Compounds of the present disclosure can be combined with another immunogenic agent, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that may be used include peptides of melanoma antigens, such as gp100, MAGE antigen, Trp-2, MARTI, and/or tyrosinase, or transfected to express the cytokine GM-CSF of tumor cells.

Compounds of the present disclosure may be used in combination with vaccination regimens to treat cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins from viruses implicated in human cancer, such as Human Papilloma Virus (HPV), Hepatitis viruses (HBV and HCV), and Kaposi's herpes Sarcoma virus (Kaposi's Herpes Sarcoma Virus, KHSV). In some embodiments, compounds of the present disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from the tumor tissue itself. In some embodiments, compounds of the present disclosure can be combined with dendritic cells to activate an effective anti-tumor response.

Compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target effector cells expressing Fc alpha or Fc gamma receptors to tumor cells. Compounds of the present disclosure may also be combined with macrocyclic peptides that activate the host immune response.

Compounds of the present disclosure can be used in combination with arginase inhibitors (eg, CB-1158).

Compounds of the present disclosure can be used in combination with bone marrow transplants to treat various tumors of hematopoietic origin.

The compounds of the present disclosure can be used as a single agent as an anticoagulant, or in combination with other anticoagulants, including (but not limited to) apixaban, dabigatran (dabigatran), edoxaban (edoxaban), fondaparinex (fondaparinex), heparin, rivaroxaban (rivaroxaban) and warfarin (warfarin).

Methods for safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Additionally, its administration is described in standard literature. For example, the administration of various chemotherapeutic agents is described in the "Physicians' Desk Reference" (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), the disclosure of which is incorporated herein by reference as if set forth in its entirety. Pharmaceutical formulations and dosage forms

When used as pharmaceuticals, the compounds provided herein may be administered in the form of a pharmaceutical composition, which refers to a compound provided herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. combination. Such compositions may be prepared in a manner well known in the medical art and may be administered by various routes, as required for oral or systemic treatment and depending on the area to be treated. Administration may be topical (including ocular and mucosal, including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), eyes, oral or parenteral. Methods of delivery to the eye may include topical administration (eye drops), subconjunctival, periocular, or intravitreal injection, or introduction via a balloon catheter or ophthalmic liner surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial (eg, intrathecal or intracerebroventricular) administration. Parenteral administration may be in single dose form or may be by, for example, a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Well-known pharmaceutical carriers, aqueous powdery or oily bases, thickeners and the like may be necessary or desired.

This application also includes pharmaceutical compositions containing one or more compounds provided herein and one or more pharmaceutically acceptable carriers as active ingredients. In preparing the compositions of the present disclosure, the active ingredient is typically mixed with an excipient, diluted with the excipient, or otherwise enclosed in such a carrier in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition may be a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (in solid form or in a liquid medium), e.g. containing In the form of ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders with up to 10% by weight of active compound.

In preparing the formulations, the active compounds can be milled to provide the appropriate particle size before being combined with the other ingredients. If the active compound is substantially insoluble, it can be ground to a particle size of less than 200 mesh. If the active compound is substantially soluble in water, the particle size can be adjusted by grinding to provide a substantially uniform distribution in the formulation, for example about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, Microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methylcellulose. Formulations may additionally include: lubricants, such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives, such as methyl- and propyl hydroxy-benzoates; sweeteners and flavoring agents. The compositions of the present disclosure may be formulated to provide rapid, sustained or delayed release of the active ingredient upon administration to a patient by employing procedures known in the art.

The compositions may be formulated in unit dosage form containing from about 5 to about 100 mg, more typically from about 10 to about 30 mg, of the active ingredient per dose. The term "unit dosage form" means physically discrete units suitable as unitary dosage forms for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient. .

The active compounds are effective over a wide dosage range and are usually administered in pharmaceutically effective amounts. It will be understood, however, that the actual amount of compound administered will generally be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration chosen, the actual compound administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms and similar situations.

For the preparation of solid compositions, such as tablets, the principal active ingredient is mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of compounds of the present disclosure. When such preformulated compositions are referred to as homogeneous, the active ingredients are generally uniformly dispersed in the composition so that the composition can be readily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing, for example, 0.1 to about 500 mg of the active ingredient of the present disclosure.

Tablets or pills of the present disclosure may be coated or otherwise compounded to provide dosage forms with the advantage of prolonged action. For example, a tablet or pill may contain an inner dosage component and an outer dosage component in the form of a coating on the former. The two components may be separated by an enteric casing that resists disintegration into the stomach and allows intact passage of the inner components into the duodenum or delayed release. A variety of materials may be used for such casings or coatings, including various polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

Liquid forms in which the compounds and compositions of the present disclosure may be combined for oral or injectable administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and Elixirs and flavored emulsions similar to pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered via the oral or nasal respiratory route to achieve local or systemic effects. The composition can be atomized by using an inert gas. The nebulized solution can be breathed directly from the nebulizing device, or the nebulizing device can be connected to a mask tent or intermittent positive pressure ventilator. Solution, suspension or powder compositions may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

The amount of compound or composition administered to a patient will vary depending on the agent, the purpose of administration (such as prophylactic or therapeutic), the patient's condition, the mode of administration, and the like. In therapeutic applications, an amount of the composition sufficient to cure or at least partially arrest symptoms of the disease and its complications may be administered to a patient who is already suffering from the disease. Effective dosages will depend on the disease condition being treated and will be judged by the attending physician based on factors such as severity of the disease, age, weight and general health of the patient, and the like.

The composition administered to the patient may be in the form of a pharmaceutical composition as described above. The compositions can be sterilized by conventional sterilization techniques, or can be sterile filtered. Aqueous solutions can be packaged for use as such or lyophilized and the lyophilized formulation combined with a sterile aqueous carrier prior to administration. The pH of the compound formulation will generally be between 3 and 11, more preferably between 5 and 9 and most preferably between 7 and 8. It will be understood that the use of certain of the aforementioned excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.

Therapeutic dosages of the compounds of the present disclosure may vary, for example, depending on the particular use for which the treatment is to be performed, the manner in which the compound is administered, the health and condition of the patient, and the judgment of the prescribing physician. The proportions or concentrations of the compounds provided herein in pharmaceutical compositions can vary depending on a variety of factors including dosage, chemical characteristics (eg, hydrophobicity), and route of administration. For example, the compounds provided herein can be provided for parenteral administration in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w/v compound. Some typical dosage ranges are about 1 µg/kg to about 1 g/kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight per day. The dosage may depend on variables such as the type and extent of the disease or condition, the general health of the particular patient, the relative biological efficacy of the selected compounds, the excipient formulation, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

The compounds provided herein may also be formulated in combination with one or more other active ingredients, which may include any pharmaceutical agent, such as antiviral agents, vaccines, antibodies, immune enhancers, immunosuppressive agents, anti-inflammatory agents, and the like. . Labeled compounds and analytical methods

Another aspect of the present disclosure relates to fluorescent dyes, spin labels, heavy metals or radiolabeled compounds provided herein, which are not only suitable for imaging, but also suitable for in vitro and in vivo analysis to locate and quantify tissue samples ( including TAM kinases in humans) and identify TAM kinase ligands by inhibitory binding of labeled compounds. Therefore, the present disclosure includes TAM kinase assays containing these labeled compounds.

The present disclosure further includes isotopically labeled compounds of the present invention. "Isotope" or "radiolabeled" compounds are compounds provided herein in which one or more atoms have an atomic mass or mass number that is different from that typically found in nature (i.e., naturally occurring). Atomic substitution or substitution. Suitable radionuclides that may be incorporated into the compounds of the present disclosure include, but are not limited to, ² H (deuterium also written as D), ³ H (tritium also written as T), ¹¹ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ¹⁸ F, ³⁵ S, ³⁶ Cl, ⁸² Br, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ¹²³ I, ¹²⁴ I, ¹²⁵ I and ¹³¹ I. The radionuclides that can be incorporated into the radiolabeled compounds of the present invention will depend on the specific application of the radiolabeled compound. For example, for in vitro TAM kinase labeling and competition assays, compounds containing ^3H , ^14C , ^82Br , ^125I , ^131I or ^35S will generally be most suitable. For radioactive imaging applications, ¹¹ C, ¹⁸ F, ¹²⁵ I, ¹²³ I, ¹²⁴ I, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br or ⁷⁷ Br will generally be most suitable.

It should be understood that a "radiolabel" or "labeled compound" is a compound containing at least one radionuclide. In some embodiments, the radionuclide is selected from the group consisting of ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br.

Synthetic methods for incorporating radioactive isotopes into organic compounds are applicable to the compounds provided herein and are well known in the art.

The radiolabeled compounds provided herein can be used in screening assays to identify/evaluate compounds. In general, a newly synthesized or identified compound (ie, a test compound) can be evaluated for its ability to reduce binding of the radiolabeled compound of the present application to TAM kinase. Therefore, the ability of a test compound to compete with a radiolabeled compound for binding to TAM kinase is directly related to its binding affinity.

The compounds of the present invention may also include all isotopes of atoms present in intermediates or final compounds. Isotopes are atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more of the constituent atoms of the compounds of the present invention may be replaced or substituted by isotopes of the atoms in natural or unnatural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the invention may be replaced or substituted by deuterium. In some embodiments, compounds include two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, or 8 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art. set

The present disclosure also includes pharmaceutical compositions, for example, suitable for the treatment or prevention of TAM-related diseases or conditions, obesity, diabetes, and other diseases mentioned herein, such compositions comprising one or more pharmaceutical compositions containing a therapeutically effective amount of Containers for pharmaceutical compositions of the compounds provided herein. It will be readily apparent to those skilled in the art that, if desired, the kits may further include one or more of various conventional pharmaceutical kit components, such as with one or more pharmaceutically acceptable carriers. Containers, other containers, etc. The kit may also include instructions, such as an insert or note, indicating the amounts of components to be administered, guidelines for dosing, and/or guidelines for mixing the components.

The invention will be described in further detail by means of specific examples. The following examples are provided for illustrative purposes and are not intended to limit the invention in any way. Those skilled in the art will readily appreciate that various non-critical parameters can be varied or modified to produce substantially the same results. As described below, the compounds of these examples were found to be inhibitors of TAM kinases.

Some of the compounds prepared were subjected to preparative LC-MS purification on a Waters mass-directed fractionation system. The basic equipment setup, experimental protocols, and control software used to operate these systems have been described in detail in the literature. See, for example, "Two-Pump At Column Dilution Configuration for Preparative LC-MS", K. Blom, J. Combi. Chem ., 4, 295 ( 2002 ); "Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification", K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem ., 5, 670 ( 2003 ); and "Preparative LC-MS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem ., 6, 874-883 ( 2004 ). Isolated compounds are typically subjected to analytical liquid chromatography mass spectrometry (LCMS) for purity checks under the following conditions: Instrument; Agilent 1100 Series, LC/MSD, Column: Waters Sunfire ^TM C ₁₈ 5 µm particle size, 2.1 ×5.0 mm, buffer: mobile phase A: 0.025% TFA in water, and mobile phase B: acetonitrile; gradient 2% to 80% B, within 3 minutes, flow rate is 2.0 mL/min.

As also shown in the Examples, some of the compounds prepared were separated on a preparative scale by reverse phase high performance liquid chromatography (RP-HPLC) or flash chromatography (silica gel) with MS detector. Typical preparative reverse phase high performance liquid chromatography (RP-HPLC) column conditions are as follows: pH = 2 purification: Waters Sunfire ^TM C ₁₈ 5 µm particle size, 19×100 mm column, with mobile phase A: 0.1 in water % TFA (trifluoroacetic acid) and mobile phase B: acetonitrile for elution; the flow rate was 30 mL/min and the separation gradient was run for each compound using a compound-specific method optimization protocol as described in the literature. Optimization [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6 , 874-883 (2004)]. The flow rate for a 30×100 mm column is typically 60 mL/min. pH _{= 10} purification: Waters The separation gradient was optimized for each compound using a compound-specific method optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem. , 6 , 874-883 (2004)]. The flow rate for a 30×100 mm column is typically 60 mL/min. Examples Example 1. N- [4-(4- amino- 7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1-(4 -Fluorophenyl )-2,5- bisoxy - 1,2,5,6,7,8 -hexahydroquinoline -3- methamide Step 1 : N-[(2,6- bisoxycyclohexylene ) methyl ] urea

To 1,3-cyclohexanedione (from Aldrich, 500 mg, 4.46 mmol) and urea (268 mg, 4.46 mmol) were dissolved in N,N -dimethylformamide (1.73 mL at 50 °C) To the mixture were added ethyl orthoformate (1.11 mL, 6.69 mmol) and acetic acid (8.9 mL). The reaction mixture was heated in a sealed tube at 90 °C for 3 h. The reaction mixture was cooled, concentrated in vacuo and left at room temperature to crystallize. The resulting precipitate was filtered by vacuum and the filter cake was washed with cold sec -BuOH to yield the desired product as a creamy white powder (536 mg, 66%). LCMS calculated for C ₈ H ₁₁ N ₂ O ₃ (M+H) ⁺ : m/z = 183.1. Experimental value: 183.1. Step 2 : Methyl 2,5- bisoxy -5,6,7,8- tetrahydro -2H- chromene -3- carboxylate

Dissolve N -[(2,6-bisoxycyclohexylene)methyl]urea (50 mg, 0.27 mmol) in anhydrous N,N -dimethylformamide (0.54 mL) with stirring Acetic acid, cyanomethyl ester (35.4 mg, 0.36 mmol) and potassium tert-butoxide (61.6 mg, 0.55 mmol) were added. The reaction mixture was heated at 100 °C for 1 h. After filtration and removal of the solvent, an oily residue was obtained as the desired product (70 mg). The crude product was used directly in the next step without further purification. LCMS calculated for C ₁₁ H ₁₁ O ₅ (M+H) ⁺ : m/z = 223.1. Experimental value: 223.1. Step 3 : 1-(4- Fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquinoline -3- carboxylic acid methyl ester

2,5-Dimensyloxy-5,6,7,8-tetrahydro- 2H -chromene-3-carboxylic acid methyl ester (30 mg, 0.14 mmol) was dissolved in tetrahydrofuran (0.4 mL) and To a solution of N,N -dimethylformamide (0.1 mL) was added p-fluoroaniline (15 mg, 0.14 mmol). The reaction mixture was stirred at room temperature for 3 h, then N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) and 4-Dimethylaminopyridine (4.1 mg, 0.034 mmol). The reaction mixture was stirred at room temperature for an additional 20 h. After filtration, the crude product was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA). material to produce the desired product (12 mg, 28%). LCMS calculated value for C ₁₇ H ₁₅ FNO ₄ (M+H) ⁺ : m/z = 316.1. Experimental value: 316.1. Step 4 : 1-(4- Fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquinoline -3- carboxylic acid

To 1-(4-fluorophenyl)-2,5-bisoxy-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid methyl ester (5.0 mg, 0.016 mmol) in To a solution in methanol (0.10 mL) was added 1.0 M sodium hydroxide in water (0.15 mL). The reaction mixture was stirred at room temperature for 30 min and the crude material was neutralized with HCl (1N) and diluted with EtOAc. The EtOAc layer was separated and the aqueous layer was washed twice with EtOAc. The combined organic layers were dried and concentrated in vacuo to yield the desired acid product as a creamy white powder. LCMS calculated value for C ₁₆ H ₁₃ FNO ₄ (M+H) ⁺ : m/z = 302.1. Experimental value: 302.2. Step 5 : 7- Vinylpyrrolo [2,1-f][1,2,4] triazin -4- amine

In a sealed flask, stir 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaboropentane (from Aldrich, 1.52 g, 9.86 mmol), 7-bromopyrrolo [2,1- f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 1.50 g, 7.04 mmol) and N,N -diisopropylethylamine (3.7 mL, 21 mmol) in 1,4-dioxane (20 mL) and water (0.97 mL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine)palladium (540 mg, 1.0 mmol) . The reaction mixture was sealed and heated in a 110°C oil bath for 60 min, filtered through a pad of celite and concentrated. The crude material was purified by Biotage silica column chromatography (40 g column, 0 to 100% EtOAc in hexanes) to yield the desired product as a white powder (541 mg, 48%). LCMS calculated for C ₈ H ₉ N ₄ (M+H) ⁺ : m/z = 161.1. Experimental value: 161.1. Step 6 : 7- Ethylpyrrolo [2,1-f][1,2,4] triazin -4- amine

To a solution of 7-vinylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (1.00 g, 6.24 mmol) in methanol (30 mL) was added the palladium mixture (1.33 g ) (5% Pd on carbon). The reaction mixture was placed on a hydrogen Parr shaker at 25 psi for 2 h. After filtration through a pad of celite, the filtrate was concentrated under vacuum to yield the desired product as a milky white powder. LCMS calculated value for C ₈ H ₁₁ N ₄ (M+H) ⁺ : m/z = 163.1. Experimental value: 163.1. Step 7 : 5- Bromo -7- ethylpyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (600 mg, 3.7 mmol) in N,N -dimethylformamide (16 mL) Add N -bromosuccinimide (395 mg, 2.22 mmol) to the solution. The resulting mixture was stirred at room temperature for 30 min, diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and concentrated _in vacuo to give the desired product as a tan solid. LCMS calculated for C ₈ H ₁₀ BrN ₄ (M+H) ⁺ : m/z = 241.0, 243.0. Experimental values: 241.0, 243.0. Step 8 : 5-(4- Aminophenyl )-7- ethylpyrrolo [2,1-f][1,2,4] triazin- 4- amine

In a sealed tube, stir 5-bromo-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (200 mg, 0.83 mmol), 4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (from Aldrich, 236 mg, 1.08 mmol) and N,N -diisopropylethylamine (0.43 mL, 2.5 mmol) in 1,4-dioxane (3.24 mL) and water (0.30 mL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine)palladium (130 mg, 0.25 mmol). The reaction mixture was sealed and heated in a 110 °C oil bath for 1 h. After filtration, the crude material was diluted with MeOH and analyzed by preparative LC- ^MS ₍ pH ⁼ 10 method; Gradient elution of OH in water) purified to yield the desired product as a light brown powder (88 mg, 42%). LCMS calculated value for C ₁₄ H ₁₆ N ₅ (M+H) ⁺ : m/z = 254.1. Experimental value: 254.1. Step 9 : N-[4-(4- amino -7- ethylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-1-(4- Fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8- hexahydroquinoline -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (3.2 mg, 0.013 mmol), 1-(4 -Fluorophenyl)-2,5-bisoxy-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (4.6 mg, 0.015 mmol) (in Example 1, Step 4 Preparation), N,N,N',N' -tetramethyl- O -(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (12 mg, 0.032 mmol) in N,N - Dimethylformamide (0.10 mL) and N,N -diisopropylethylamine (5.0 mg, 0.04 mmol) were mixed together and stirred at room temperature for 20 min. The mixture was _filtered , ^concentrated and analyzed by preparative LC- ^MS (pH = 10 method; Gradient elution) was purified to yield the desired product as a white powder (1.6 mg, 20%). LCMS calculated for C ₃₀ H ₂₆ FN ₆ O ₃ (M+H) ⁺ : m/z = 537.2. Experimental value: 537.2. Example 2. N -[4-(4- Amino -7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1-[(1 R )-2- hydroxy -1- phenylethyl ]-2- side oxy -1,2- dihydropyridine -3- methamide Step 1 : 1-[(1R)-2- hydroxy -1- phenylethyl ]-2- side oxy -1,2- dihydropyridine -3- carboxylic acid

[(2 E )-3-Methoxypropylene-2-en-1-yl]malonate dimethyl ester (from Acros Organics, 0.20 g, 1.00 mmol) was dissolved in methanol (1.8 mL) and mixed with ( 2R )-2-Amino-2-phenylethanol (0.14 g, 1.00 mmol) and N,N -diisopropylethylamine (0.55 mL, 3.2 mmol) were combined. The reaction mixture was sealed and stirred at 130 °C for 2 h. The reaction mixture was then combined with 2.0 M sodium hydroxide in methanol (5.0 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and stirred continuously at room temperature for 2 h. The crude material was neutralized with HCl (3N) and extracted 3 times with EtOAc. The combined organic layers were dried, filtered and concentrated under vacuum to give the desired product as a light brown gum. LCMS calculated for C ₁₄ H ₁₄ NO ₄ (M+H) ⁺ : m/z = 260.1. Experimental value: 260.1. Step 2 : N-[4-(4- amino -7- ethylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-1-[(1R )-2- hydroxy -1- phenylethyl ]-2- side oxy -1,2- dihydropyridine -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (3.0 mg, 0.012 mmol) (in Example HF1, Prepared in step 8), 1-[(1 R )-2-hydroxy-1-phenylethyl]-2-sideoxy-1,2-dihydropyridine-3-carboxylic acid (3.6 mg, 0.014 mmol) , N,N,N',N' -tetramethyl- O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (11.2 mg, 0.03 mmol) in N,N -dimethyl Formamide (0.10 mL) and N,N -diisopropylethylamine (4.6 mg, 0.035 mmol) were mixed together and stirred at room temperature for 60 min. The reaction mixture was filtered, concentrated ^and analyzed by preparative LC- ^MS (pH = 10 _method ; Gradient elution) was purified to yield the desired product as a white powder (2.0 mg, 34%). LCMS calculated for C ₂₈ H ₂₇ N ₆ O ₃ (M+H) ⁺ : m/z = 495.2. Experimental value: 495.2. Example 3. N- [4-(4- amino -7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1-[(1 R )-2- hydroxy -1- methylethyl ]-2- side oxy -1,2- dihydropyridine -3- methamide Step 1 : 1-[(1R)-2- Hydroxy -1- methylethyl ]-2- Pendantoxy -1,2- dihydropyridine -3- carboxylic acid

[( 2E )-3-Methoxypropylene-2-en-1-yl]dimethylmalonate (from Acros Organics, 200 mg, 1.00 mmol) was dissolved in methanol (1.82 mL) and mixed with ( R )-(-)-2-Amino-1-propanol (from Aldrich, 75.0 mg, 1.00 mmol) and N,N -diisopropylethylamine (0.55 mL, 3.2 mmol) were combined. The reaction mixture was sealed and stirred at 130 °C for 2 h. The reaction mixture was then combined with 2.0 M sodium hydroxide in methanol (5.0 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and stirred continuously at room temperature for 2 h. The reaction mixture was acidified with 5.0 mL HCl (3 N) and concentrated in vacuo to remove the solvent. The residue was washed with THF and EtOAc, dried, filtered and concentrated in vacuo to give the desired product as a creamy white powder. LCMS calculated for C ₉ H ₁₂ NO ₄ (M+H) ⁺ : m/z = 198.1. Experimental value: 198.1. Step 2 : N-[4-(4- amino -7- ethylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-1-[(1R )-2- hydroxy -1- methylethyl ]-2- side oxy -1,2- dihydropyridine -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (5.0 mg, 0.020 mmol) (in Example HF1, Prepared in step 8), 1-[(1 R )-2-hydroxy-1-methylethyl]-2-pendantoxy-1,2-dihydropyridine-3-carboxylic acid (4.7 mg, 0.024 mmol) , N,N,N',N' -tetramethyl- O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (18.8 mg, 0.05 mmol) in N,N -dimethyl methylformamide (0.1 mL) and N,N -diisopropylethylamine (7.7 mg, 0.06 mmol) were mixed together and stirred at room temperature for 30 min. The mixture was _filtered , ^concentrated and analyzed by preparative LC- ^MS (pH = 10 method; Gradient elution) was purified to yield the desired product as a white powder (2.0 mg, 23%). LCMS calculated for C ₂₃ H ₂₅ N ₆ O ₃ (M+H) ⁺ : m/z = 433.2. Experimental value: 433.2. Example 4. N -[4-(4- Amino -7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1-[(1 R )-1-( hydroxymethyl ) propyl ]-2- side oxy -1,2- dihydropyridine -3- methamide Step 1 : 1-[(1R)-1-( hydroxymethyl ) propyl ]-2- Pendantoxy -1,2- dihydropyridine -3- carboxylic acid

[( 2E )-3-Methoxypropylene-2-en-1-yl]dimethylmalonate (from Acros Organics, 200 mg, 1.00 mmol) was dissolved in methanol (1.82 mL) and mixed with ( 2R )-2-Aminobutan-1-ol (89.0 mg, 1.00 mmol) and N,N -diisopropylethylamine (0.55 mL, 3.2 mmol) were combined. The reaction mixture was sealed and stirred at 130 °C for 2 h. The reaction mixture was then combined with 2.0 M sodium hydroxide in methanol (5.0 mL) and 2.0 M sodium hydroxide in water (5.0 mL) and stirred continuously at room temperature for 1 h. The reaction mixture was acidified with 5.0 mL HCl (3 N) and concentrated in vacuo to remove the solvent. The residue was washed with THF and EtOAc, dried, filtered and concentrated in vacuo to give the desired product as a creamy white powder. LCMS calculated for C ₁₀ H ₁₄ NO ₄ (M+H) ⁺ : m/z = 212.1. Experimental value: 212.1. Step 2 : N-[4-(4- amino -7- ethylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-1-[(1R )-1-( hydroxymethyl ) propyl ]-2- side oxy -1,2- dihydropyridine -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (5.0 mg, 0.020 mmol) (in Example HF1, Prepared in step 8), 1-[(1 R )-1-(hydroxymethyl)propyl]-2-sideoxy-1,2-dihydropyridine-3-carboxylic acid (5.0 mg, 0.024 mmol), N,N,N',N' -tetramethyl- O -(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (18.8 mg, 0.049 mmol) in N,N -dimethyl Formamide (0.1 mL) and N,N -diisopropylethylamine (7.7 mg, 0.06 mmol) were mixed together and stirred at room temperature for 30 min. The reaction mixture was filtered, concentrated ^and analyzed by preparative LC- ^MS (pH = 10 _method ; Gradient elution) was purified to yield the desired product as a white powder (1.7 mg, 19%). LCMS calculated for C ₂₄ H ₂₇ N ₆ O ₃ (M+H) ⁺ : m/z = 447.2. Experimental value: 447.2. Example 5. N -[4-(4- Amino- 7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1- phenylmethyl -2- Pendantoxy -1,2- dihydropyridine -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (4.6 mg, 0.02 mmol) (in Example 1, (prepared in step 8), 1-benzyl-2-pendantoxy-1,2-dihydropyridine-3-carboxylic acid (from Aurum Pharmatech, 5 mg, 0.02 mmol), N,N,N',N' -Tetramethyl- O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (17.3 mg, 0.05 mmol) in N,N -dimethylformamide (0.1 mL) and N , N -diisopropylethylamine (7 mg, 0.05 mmol) were mixed together and stirred at room temperature for 30 min. The reaction mixture was filtered, concentrated ^and analyzed by preparative LC- ^MS (pH = 10 _method ; Gradient elution) was purified to yield the desired product as a white powder (2.4 mg, 28%). LCMS calculated for C ₂₇ H ₂₅ N ₆ O ₂ (M+H) ⁺ : m/z = 465.2. Experimental value: 465.2. Example 6. N- [4-(4- amino -7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1 - methyl- 2- Pendantoxy -1,2- dihydropyridine -3- methamide

5-(4-Aminophenyl)-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (4 mg, 0.02 mmol) (in Example 1, Prepared in Step 8), 1-Methyl-2-Pendantoxy-1,2-dihydropyridine-3-carboxylic acid (from Synthonix, 2.9 mg, 0.02 mmol), N,N,N',N' -tetrahydrofuran Methyl- O -(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (12 mg, 0.03 mmol) in N,N -dimethylformamide (0.1 mL) and triethylamine (4.8 mg, 0.05 mmol) and stirred at room temperature for 30 min. The reaction mixture was filtered, concentrated ^and analyzed by preparative LC- ^MS (pH = 10 _method ; Gradient elution) was purified to yield the desired product as a white powder (1.6 mg, 26%). LCMS calculated for C ₂₁ H ₂₁ N ₆ O ₂ (M+H) ⁺ : m/z = 389.2. Experimental value: 389.2. Example 7a. N -{4-[4- Amino- 7-( cis -4- hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-2- Pendant oxy -1- phenyl -1,2- dihydropyridine -3- carboxamide Example 7b. N -{4-[4- amino -7-( trans -4- hydroxycyclohexyl) ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methyl amide Step 1 : 2- Pendant oxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid methyl ester

2-Pendantoxy-1,2-dihydropyridine-3-carboxylic acid methyl ester (from Aldrich, 1.50 g, 9.80 mmol), phenylboronic acid (3.6 g, 29 mmol), A mixture of activated 4Å molecular sieve (2.8 g, 12 mmol) and copper acetate (3.6 g, 20.0 mmol) in dichloromethane (60 mL). The reaction mixture was stirred at room temperature for 60 h and filtered through a pad of celite. The filtrate was concentrated under vacuum. The crude product was purified by Biotage silica gel chromatography (0 to 100% ethyl acetate in hexanes) to yield the desired product as a white powder (1.26 g, 56%). LCMS calculated for C ₁₃ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 230.1. Experimental value: 230.1. Step 2 : 2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

2-Pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid methyl ester (800 mg, 3.49 mmol) was dissolved in tetrahydrofuran (7.4 mL) and methanol (3.7 mL). The mixture was then treated with 1.0 M sodium hydroxide in water (14.0 mL) and stirred at room temperature for 30 min. The reaction mixture was neutralized with HCl (12 M) to pH = 6-7. The solvent was removed under vacuum and the product precipitated. The solid was collected by vacuum filtration and the filter cake was washed with water and dried overnight to yield the desired acid product as a white powder (636 mg, 85%). LCMS calculated for C ₁₂ H ₁₀ NO ₃ (M+H) ⁺ : m/z = 216.1. Experimental value: 216.1. Step 3 : 2- Pendant oxy -1- phenyl -N-[4-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentan -2- yl ) phenyl ]-1,2- dihydropyridine -3- methamide

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (from Aldrich, 214 mg, 0.98 mmol) and the 2-side oxy- To a mixture of 1-phenyl-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.93 mmol) in N,N -dimethylformamide (4.5 mL) was added triethylamine (194 μL, 1.4 mmol), followed by the addition of N,N,N',N' -tetramethyl- O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (424 mg, 1.12 mmol). The resulting reaction mixture, which quickly turned into a solid mixture, was stirred at room temperature for 1 h. The solid was filtered and washed with water. Drying by vacuum gave the desired product as a white solid (306 mg, 79%). LCMS calculated for C ₂₄ H ₂₆ BN ₂ O ₄ (M+H) ⁺ : m/z = 417.2. Experimental value: 417.2. Step 4 : 7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohex - 1- en - 1- yl ) pyrrolo [2,1- f ][1,2, 4] Triazin -4- amine

tert-Butyl(dimethyl){[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-ene- 1-yl]oxy}silane (450 mg, 1.33 mmol), 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (283 mg, 1.33 mmol), carbonic acid Sodium (470 mg, 4.4 mmol) and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (101 mg, 0.133 mmol) in tert-butanol (4.0 mL) and The mixture in water (1.5 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h and then at 95 °C overnight. The mixture was diluted with ethyl acetate, washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and _concentrated . The product was purified by Biotage silica gel chromatography (0 to 50% EtOAc in hexane) to yield the desired product as a creamy white powder (242.3 mg, 53%). LCMS calculated value for C ₁₈ H ₂₉ N ₄ OSi (M+H) ⁺ : m/z = 345.2. Experimental value: 345.2. Step 5 : 7-(4-{[ tert-Butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohex-1-en-1-yl)pyrrolo[2,1 -f ][1,2,4] To a solution of triazin-4-amine (230 mg, 0.67 mmol) in methanol (2.8 mL) and tetrahydrofuran (1.4 mL) was added a palladium mixture (4.6 mg) (10% Pd on carbon). The reaction mixture was evacuated and placed under a hydrogen balloon for 1 h. After filtration through a pad of celite, the filtrate was concentrated under vacuum to yield the desired product (161.9 mg, 70%). LCMS calculated value for C ₁₈ H ₃₁ N ₄ OSi (M+H) ⁺ : m/z = 347.2. Experimental value: 347.2. Step 6 : 5- bromo -7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1,2,4] triazine -4- amine

To 7-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (80.0 To a solution of N,N -dimethylformamide (1.0 mL) was added N -bromosuccinimide (39.0 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered again and concentrated under vacuum to give the desired product as a tan solid. LCMS calculated value for C ₁₈ H ₃₀ BrN ₄ OSi (M+H) ⁺ : m/z = 425.1, 427.1. Experimental values: 425.1, 427.1. Step 7 : N-{4-[4- amino - 7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide

2-Pendantoxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]- 1,2-Dihydropyridine-3-carboxamide (48.9 mg, 0.12 mmol) (prepared in Example 7, step 3), 5-bromo-7-(4-{[tert-butyl(dimethyl )silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (50 mg, 0.12 mmol), sodium carbonate (42 mg, 0.39 mmol) and [1,1'-Bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (13.4 mg, 0.018 mmol) in tert-butanol (0.35 mL) and water (0.13 mL) Degas with nitrogen, then stir and heat at 110 °C for 1 h. The mixture was diluted with ethyl acetate, washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and _concentrated . The crude product was purified by Biotage silica gel chromatography (0 to 100% EtOAc in hexane) to yield the desired product as a white powder (34 mg, 46%). LCMS calculated for C ₃₆ H ₄₃ N ₆ O ₃ Si (M+H) ⁺ : m/z = 635.3. Experimental value: 635.3. Step 8 : N-{4-[4- Amino- 7-(4- hydroxycyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ] phenyl }- 2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide

N -{4-[4-Amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2 ,4]triazin-5-yl]phenyl}-2-side oxy-1-phenyl-1,2-dihydropyridine-3-methamide (34 mg, 0.05 mmol) in tetrahydrofuran (0.2 mL ) was treated with 4.0 M hydrochloric acid in dioxane (0.9 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 30 min. The crude material (1:4 ratio of cis and trans isomers) was concentrated in vacuo and analyzed by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm , 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired cis isomer (9.2 mg, 33%). The minor trans isomer (3.5 mg, 12%) was also isolated. The retention time (RT) of the minor trans isomer = RT = 1.189 min, the first peak leaving the column; the RT of the major cis isomer = 1.216 min, the second peak leaving the column. LCMS calculated for C ₃₀ H ₂₉ N ₆ O ₃ (M+H) ⁺ : m/z = 521.2. Experimental value: 521.2. ¹ H NMR (500 MHz, dmso) δ 12.06 (s, 1H), 8.62 (dd, J = 7.3, 2.2 Hz, 1H), 8.14 (dd, J = 6.6, 2.2 Hz, 1H), 7.90 (s, 1H ), 7.82 (d, J = 8.6 Hz, 2H), 7.66-7.52 (m, 6H), 7.47 (d, J = 8.5 Hz, 2H), 6.78-6.72 (m, 2H), 6.55 (s, 1H) , 4.38 (d, J = 2.9 Hz, 1H), 3.92 (s, 1H), 3.62 (d, J = 6.5 Hz, 1H), 3.16 (t, J = 11.4 Hz, 1H), 1.99-1.84 (m, 2H), 1.84-1.70 (m, 4H), 1.62 (t, J = 12.2 Hz, 1H). Example 8. N -[4-(4- Amino- 7- methylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-2- side oxy group -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 7- methylpyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (from J&W Pharm Lab, 150 mg, 0.70 mmol) in tetrahydrofuran at room temperature under _N (2.86 mL) was added 4(triphenylphosphine)palladium(0) (163 mg, 0.14 mmol). The mixture in the sealed flask was evacuated and refilled several times with _N , followed by the addition of 2.0 M dimethylzinc in toluene (5.3 mL, 10 mmol) at room temperature. The reaction mixture was heated at 90 °C for 4 h. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated in vacuo to yield crude material, which was analyzed by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30× ₁₀₀ mm, 60 mL/min, gradient elution with MeCN and water with 0.15% _NH4OH ) to yield the desired product as a white powder (29.2 mg, 28%). LCMS calculated for C ₇ H ₉ N ₄ (M+H) ⁺ : m/z = 149.1. Experimental value: 149.1. Step 2 : 5- Bromo -7- methylpyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-methylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (29.2 mg, 0.20 mmol) in N,N -dimethylformamide (0.85 mL) N -bromosuccinimide (33.3 mg, 0.19 mmol) was added to the solution. The resulting mixture was stirred at room temperature for 15 min and the reaction mixture was diluted with EtOAc, filtered, then washed with saturated _NaHCO3 , water, dried, filtered and concentrated in vacuo to give the desired product as a creamy white powder. LCMS calculated for C ₇ H ₈ BrN ₄ (M+H) ⁺ : m/z = 227.0, 229.0. Experimental values: 227.0, 229.0. Step 3 : N-[4-(4- amino -7- methylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-2- side oxy group -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, combine 5-bromo-7-methylpyrrolo[2,1 -f ][1,2,4]triazin-4-amine (5.6 mg, 0.02 mmol), 2-side oxy -1-phenyl- N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydro A mixture of pyridine-3-carboxamide (8.0 mg, 0.02 mmol) (prepared in Example 7, step 3) and N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) was dissolved in 1,4-diisopropylethylamine (0.01 mL, 0.06 mmol). The mixture was stirred together with oxane (0.14 mL) and water (20 μL) and rinsed with _N2 bubbles for 5 min, after which bis(tri-tert-butylphosphine)palladium (4.7 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.8 mg, 36%). LCMS calculated for C ₂₅ H ₂₁ N ₆ O ₂ (M+H) ⁺ : m/z = 437.2. Experimental value: 437.2. Example 9. N -[4-(4- Amino- 7- methylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-1-(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxamide Step 1 : 1-(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxylic acid methyl ester

2-Pendantoxy-1,2-dihydropyridine-3-carboxylic acid methyl ester (from Aldrich, 1.50 g, 9.8 mmol), 4-fluorophenylboronic acid (from Aldrich, 4.1 g, 29 mmol), activated 4Å molecular sieve A mixture of (2.8 g, 12 mmol) and copper acetate (3.6 g, 20 mmol) in dichloromethane (60 mL) was treated with pyridine (2.4 mL) and then stirred at room temperature for 18 h. The mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude material was purified by Biotage silica column chromatography (0 to 100% ethyl acetate in hexane) to yield the desired product as a milky white gum (1.33 g, 55%). LCMS calculated value for C ₁₃ H ₁₁ FNO ₃ (M+H) ⁺ : m/z = 248.1. Experimental value: 248.1. Step 2 : 1-(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxylic acid

Dissolve 1-(4-fluorophenyl)-2-side-oxy-1,2-dihydropyridine-3-carboxylic acid methyl ester (800 mg, 3.24 mmol) in tetrahydrofuran (6.82 mL) and methanol (3.41 mL) middle. The mixture was then treated with 1.0 M sodium hydroxide in water (12.9 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was neutralized with HCl (12 M) to pH = 6-7. The solvent was removed under vacuum and the product was allowed to precipitate. The solid was collected by vacuum filtration and the filter cake was washed with water and dried overnight to yield the desired acid product as a white powder (540 mg, 72%). LCMS calculated value for C ₁₂ H ₉ FNO ₃ (M+H) ⁺ : m/z = 234.1. Experimental value: 234.1. Step 3 : 1-(4- fluorophenyl )-2- side oxy -N-[4-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentane -2) -yl ) phenyl ]-1,2- dihydropyridine - 3- methamide

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (from Aldrich, 197.3 mg, 0.90 mmol) and 1-(4-fluoro Phenyl)-2-Pendantoxy-1,2-dihydropyridine-3-carboxylic acid (from Aldrich, 200 mg, 0.86 mmol) in a mixture of N,N -dimethylformamide (4.0 mL) Triethylamine (180 μL, 1.3 mmol) was added, followed by N,N,N',N' -tetramethyl -O- (7-azabenzotriazol-1-yl)ureonium hexafluorophosphate ( 391 mg, 1.03 mmol). The resulting mixture, which quickly became a solid mixture, was stirred at room temperature for 1 h. The solid was filtered and washed with water. Drying by vacuum gave the desired product as a white solid (343 mg, 92%). LCMS calculated for C ₂₄ H ₂₅ BFN ₂ O ₄ (M+H) ⁺ : m/z = 435.2. Experimental value: 435.2. Step 4 : N-[3- fluoro -4-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentan -2- yl ) phenyl ]-2- side oxy group -1- phenyl -1,2- dihydropyridine -3- methamide

To 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (from Aldrich, 289.2 mg, 1.22 mmol) and 2- Pendant oxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (250 mg, 1.16 mmol) (prepared in Example 7, Step 2) in N,N -dimethylformamide (5.0 mL), add triethylamine (243 μL, 1.74 mmol), and then add N,N, N',N' -tetramethyl- O- (7-azabenzotriazol-1-yl) Ureonium hexafluorophosphate (530 mg, 1.39 mmol). The resulting mixture, which quickly became a solid mixture, was stirred at room temperature for 1 h. The solid was filtered and washed with water. Drying by vacuum gave the desired product as a white solid (335 mg, 66%). LCMS calculated for C ₂₄ H ₂₅ BFN ₂ O ₄ (M+H) ⁺ : m/z = 435.2. Experimental value: 435.2. Step 5 : 1-(4- fluorophenyl )-N-[3- fluoro -4-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentan -2- yl ) Phenyl ]-2- Pendantoxy -1,2- dihydropyridine -3- methamide

To 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (from Aldrich, 213.5 mg, 0.90 mmol) and 1- (4-Fluorophenyl)-2-pendantoxy-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.86 mmol) (prepared in Example 9, step 2) in N,N -dimethyl To a mixture of formamide (4.7 mL) was added triethylamine (179 μL, 1.29 mmol), followed by N,N,N',N' -tetramethyl- O- (7-azabenzotriazole -1-yl)ureonium hexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture, which quickly became a solid mixture, was stirred at room temperature for 1 h. The solid was filtered and washed with water. Drying by vacuum gave the desired product as a white solid (305 mg, 79%). LCMS calculated for C ₂₄ H ₂₄ BF ₂ N ₂ O ₄ (M+H) ⁺ : m/z = 453.2. Experimental value: 453.2. Step 6 : N-[4-(4- amino -7- methylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-1-(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxamide

In a sealed tube, 5-bromo-7-methylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (5 mg, 0.02 mmol) (in Example 8, step Prepared in 2), 1-(4-fluorophenyl)-2-side oxy- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane) -2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (8 mg, 0.02 mmol) (prepared in Example 9, step 3) and N,N -diisopropylethylamine (0.01 mL, 0.05 mmol) was stirred together in 1,4-dioxane (0.13 mL) and water (20 μL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine)palladium (4.2 mg, 0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.4 mg, 32%). LCMS calculated for C ₂₅ H ₂₀ FN ₆ O ₂ (M+H) ⁺ : m/z = 455.2. Experimental value: 455.2. Example 10. N -[4-(4- Amino- 7- methylpyrrolo [2,1- f ][1,2,4] triazin -5- yl )-3- fluorophenyl ]-2 -Pendant oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-methylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (5 mg, 0.016 mmol) (in Example 8, step Prepared in 2), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2-side Oxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (7.5 mg, 0.017 mmol) (prepared in Example 9, Step 4) and N,N -diisopropylethylamine ( A mixture of 0.01 mL, 0.049 mmol) was stirred together in 1,4-dioxane (0.128 mL) and water (20 μL) and flushed with N for 5 min, after which _bis (tri-tert-butylphosphine)palladium ( 4.2 mg, 0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (1.7 mg, 23%). LCMS calculated for C ₂₅ H ₂₀ FN ₆ O ₂ (M+H) ⁺ : m/z = 455.2. Experimental value: 455.2. Example 11. N- [ 4-(4- Amino- 7- methylpyrrolo [2,1- f ][1,2,4] triazin -5- yl )-3- fluorophenyl ]-1 -(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxamide

In a sealed tube, 5-bromo-7-methylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (3.2 mg, 0.01 mmol) (in Example 8, step Prepared in 2), 1-(4-fluorophenyl) -N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2 -yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-carboxamide (5 mg, 0.01 mmol) (prepared in Example 9, step 5) and N,N -diiso A mixture of propylethylamine (0.01 mL, 0.04 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with _N for 5 min before adding bis(tritertiary butyl) (2.7 mg, 0.005 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.0 mg, 40%). LCMS calculated for C ₂₅ H ₁₉ F ₂ N ₆ O ₂ (M+H) ⁺ : m/z = 473.2. Experimental value: 473.2. Example 12. N -[4-(4- Amino- 7- ethylpyrrolo [2,1- f ][1,2,4] triazin -5- yl )-3- fluorophenyl ]-2 -Pendant oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-ethylpyrrolo[2,1- f ][1,2,4]triazin-4-amine (6 mg, 0.018 mmol) (in Example 1, step Prepared in 7), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2-side Oxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (8.3 mg, 0.02 mmol) (prepared in Example 9, step 4) and N,N -diisopropylethylamine ( A mixture of 0.02 mL, 0.11 mmol) was stirred together in 1,4-dioxane (0.14 mL) and water (20 μL) and flushed with _N for 5 min, after which bis(tri-tert-butylphosphine)palladium ( 4.6 mg, 0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.4 mg, 28%). LCMS calculated for C ₂₆ H ₂₂ FN ₆ O ₂ (M+H) ⁺ : m/z = 469.2. Experimental value: 469.2. Example 13. N -{4-[4- Amino -7-( tetrahydro -2 H -pyran -4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5 -yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine - 3- methamide Step 1 : 7-(3,6- dihydro -2H- piran -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 4- amine

In a sealed flask, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-3,6-dihydro- 2H -piper Pyramide (from Aldrich, 0.64 g, 3.01 mmol), 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 0.500 g, 2.35 mmol ) and N,N -diisopropylethylamine (1.2 mL, 7.0 mmol) were stirred together in 1,4-dioxane (6 mL) and water (0.32 mL) and flushed with N for ₅ min. Bis(tri-tert-butylphosphine)palladium (100 mg, 0.24 mmol) was then added. The reaction mixture was then sealed and heated at 120°C for 4 h, filtered through a pad of celite and concentrated. The crude material was purified by Biotage silica column chromatography (40 g column, 0 to 100% EtOAc in hexanes) to yield the desired product as a white powder (168.5 mg, 33%). LCMS calculated value for C ₁₁ H ₁₃ N ₄ O (M+H) ⁺ : m/z = 217.1. Experimental value: 217.1. Step 2 : 7-( tetrahydro -2H- pyran -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-(3,6-dihydro-2 H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (120 mg, 0.55 mmol) To a solution in methanol (2.67 mL) and THF (1.3 mL) was added the palladium mixture (120 mg) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 2 hours. After filtration through a pad of celite, the filtrate was concentrated under vacuum to yield the desired product as a white powder (90.2 mg, 75%). LCMS calculated for C ₁₁ H ₁₅ N ₄ O (M+H) ⁺ : m/z = 219.1. Experimental value: 219.1. Step 3 : 5- bromo -7-( tetrahydro -2H- piran -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-(tetrahydro-2 H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (50 mg, 0.23 mmol) in N,N To a solution of -dimethylformamide (0.99 mL) was added N -bromosuccinimide (41 mg, 0.23 mmol). The resulting mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered again and concentrated under vacuum to give the desired product as a tan solid. LCMS calculated value for C ₁₁ H ₁₄ BrN ₄ O (M+H) ⁺ : m/z = 297.0, 299.0. Experimental values: 297.0, 299.0. Step 4 : N-{4-[4- amino- 7-( tetrahydro -2H- pyran -4- yl ) pyrrolo [2,1-f][1,2,4] triazine -5- base ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(tetrahydro- 2H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine ( 6 mg, 0.02 mmol), 2-Pendantoxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2- phenyl]-1,2-dihydropyridine-3-carboxamide (8.8 mg, 0.02 mmol) (prepared in Example 7, step 3) and N,N -diisopropylethylamine (0.01 mL , 0.06 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with N ₂ for 5 min, then bis(tri-tert-butylphosphine)palladium (5.2 mg ,0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (3.2 mg, 31%). LCMS calculated for C ₂₉ H ₂₇ N ₆ O ₃ (M+H) ⁺ : m/z = 507.2. Experimental value: 507.2. Example 14. N -{4-[4- Amino -7-( tetrahydro -2 H -pyran -4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5 -yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine - 3- methamide

In a sealed tube, 5-bromo-7-(tetrahydro- 2H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine ( 6 mg, 0.02 mmol) (prepared in Example 13, step 3), 1-(4-fluorophenyl)-2-pendantoxy- N -[4-(4,4,5,5-tetramethyl -1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (9.2 mg, 0.02 mmol) (prepared in Example 9, step 3 ) and N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) were stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with N for ₅ min. Bis(tri-tert-butylphosphine)palladium (5.2 mg, 0.01 mmol) was then added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (4.8 mg, 45%). LCMS calculated for C ₂₉ H ₂₆ FN ₆ O ₃ (M+H) ⁺ : m/z = 525.2. Experimental value: 525.2. Example 15. N -{4-[4- Amino -7-( tetrahydro -2 H -pyran -4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5 -yl ] -3- fluorophenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(tetrahydro- 2H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine ( 5 mg, 0.02 mmol) (prepared in Example 13, step 3), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane) -2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (7.3 mg, 0.017 mmol) (prepared in Example 9, step 4) A mixture of N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) was stirred in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with N for ₅ min. Bis(tri-tert-butylphosphine)palladium (4.3 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 2 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (6.4 mg, 72%). LCMS calculated for C ₂₉ H ₂₆ FN ₆ O ₃ (M+H) ⁺ : m/z = 525.2. Experimental value: 525.2. Example 16. N -{4-[4- Amino -7-( tetrahydro -2 H -pyran -4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5 -yl ] -3- fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(tetrahydro- 2H -piran-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine ( 6 mg, 0.02 mmol) (prepared in Example 13, step 3), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboropentan-2-yl)phenyl]-2-pentanoxy-1,2-dihydropyridine-3-methamide (9.6 mg, 0.02 mmol) (in Example 9, A mixture of (prepared in step 5) and N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) with N ₂ Rinse for 5 min before adding bis(tri-tert-butylphosphine)palladium (5.2 mg, 0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (4.4 mg, 40%). LCMS calculated for C ₂₉ H ₂₅ F ₂ N ₆ O ₃ (M+H) ⁺ : m/z = 543.2. Experimental value: 543.2. Example 17a. N -{4-[4- Amino- 7-( cis -4- hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide Example 17b. N -{4-[4- amino - 7- ( trans- 4- Hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1 ,2- dihydropyridine -3- methamide Step 1 : N-{4-[4- amino - 7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2, 4] Triazin-4-amine (5 mg, 0.012 mmol) (prepared in Example 7, step 6), 1-(4-fluorophenyl)-2-side oxy- N -[4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (5.4 mg, 0.012 mmol) A mixture of (prepared in Example 9, step 3) and N,N -diisopropylethylamine (0.012 mL, 0.07 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) Stir and _flush with N for 5 min before adding bis(tri-tert-butylphosphine)palladium (3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was used directly in the next step. LCMS calculated for C ₃₆ H ₄₂ FN ₆ O ₃ Si (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. Step 2 : N-{4-[4- Amino- 7-(4- hydroxycyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ] phenyl }- 1-(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- methamide

N -{4-[4-Amino-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2 ,4]triazin-5-yl]phenyl}-1-(4-fluorophenyl)-2-side-oxy-1,2-dihydropyridin-3-methamide (7.7 mg, 0.012 mmol) A solution in methanol (0.05 mL) was treated with 4.0 M hydrochloric acid in dioxane (0.20 mL). The reaction mixture was stirred at room temperature for 20 min. The _crude material was concentrated in ^vacuo and analyzed by preparative LC- ^MS (pH = 10 method; Gradient elution) was purified to yield the desired product (cis isomer) as a white powder (2.8 mg, 44%). RT of the major cis isomer = 2.047 min, leaving the column as the second peak. The trans isomer is the minor product and is the first peak leaving the column. The trans isomer was not separated. LCMS calculated for C ₃₀ H ₂₈ FN ₆ O ₃ (M+H) ⁺ : m/z = 539.2. Experimental value: 539.2. Example 18a. N -{4-[4- amino- 7-( cis -4- hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3 -Fluorophenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide Example 18b. N -{4-[4- amino - 7-( trans -4 -Hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] -3- fluorophenyl }-2- side oxy -1- phenyl -1,2 -Dihydropyridine - 3- methamide Step 1 : N-{4-[4- amino - 7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ]-3- fluorophenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2, 4] Triazin-4-amine (6 mg, 0.014 mmol) (prepared in Example 7, step 6), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide (6.1 mg, 0.014 mmol) ( A mixture of (prepared in Example 9, Step 4) and N,N -diisopropylethylamine (0.014 mL, 0.08 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL). and _flushed with N for 5 min, after which bis(tri-tert-butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was used directly in the next step. LCMS calculated for C ₃₆ H ₄₂ FN ₆ O ₃ Si (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. Step 2 : N-{4-[4- Amino- 7-(4- hydroxycyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ]-3- fluoro Phenyl }-2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide

N -{4-[4-Amino-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2 ,4]triazin-5-yl]-3-fluorophenyl}-2-side oxy-1-phenyl-1,2-dihydropyridine-3-methamide (9.2 mg, 0.014 mmol) in A solution in methanol (0.06 mL) was treated with 4.0 M hydrochloric acid in dioxane (0.24 mL). The reaction mixture was stirred at room temperature for 30 min. The crude material was concentrated under vacuum and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient with MeCN and water with 0.1% TFA elution) purification to yield the desired product (cis isomer) as a white powder. RT of cis isomer = 1.208 min, leaving the second peak of the column. LCMS calculated for C ₃₀ H ₂₈ FN ₆ O ₃ (M+H) ⁺ : m/z = 539.2. Experimental value: 539.2. Example 19a. N -{4-[4- amino- 7-( cis -4- hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3 -Fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide Example 19b. N -{4-[4- amino - 7 -( trans -4- hydroxycyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3- fluorophenyl }-1-(4- fluorophenyl ) -2- Pendantoxy -1,2- dihydropyridine -3- methamide Step 1 : N-{4-[4- amino - 7-(4-{[ tert-butyl ( dimethyl ) silyl ] oxy } cyclohexyl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ]-3- fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2, 4] Triazin-4-amine (5 mg, 0.012 mmol) (prepared in Example 7, step 6), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2-pentoxy-1,2-dihydropyridine-3-methamide (5.6 mg , 0.012 mmol) (prepared in Example 9, Step 5) and N,N -diisopropylethylamine (0.012 mL, 0.07 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) and _rinsed with N for 5 min, after which bis(tri-tert-butylphosphine)palladium (3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 100 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was used directly in the next step. LCMS calculated for C ₃₆ H ₄₁ F ₂ N ₆ O ₃ Si (M+H) ⁺ : m/z = 671.3. Experimental value: 671.3. Step 2 : N-{4-[4- Amino- 7-(4- hydroxycyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ]-3- fluoro Phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

N -{4-[4-Amino-7-(4-{[ tert-butyl (dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1- f ][1,2 ,4]triazin-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-side oxy-1,2-dihydropyridine-3-methamide (7.9 mg A solution of , 0.012 mmol) in methanol (0.05 mL) was treated with 4.0 M hydrochloric acid in dioxane (0.2 mL). The reaction mixture was stirred at room temperature for 30 min. The _crude material was concentrated in ^vacuo and analyzed by preparative LC- ^MS (pH = 10 method; Gradient elution) was purified to yield the desired product (cis isomer) as a white powder (1.8 mg, 27%). RT of the major cis isomer = 2.114 min, leaving the column as the second peak. The trans isomer is not separated and is the first peak leaving the column. LCMS calculated for C ₃₀ H ₂₇ F ₂ N ₆ O ₃ (M+H) ⁺ : m/z = 557.2. Experimental value: 557.2. Example 20. N -{4-[4- amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 7-(1- methyl -1,2,3,6- tetrahydropyridin - 4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 4- amine

7-Bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 208 mg, 0.97 mmol), 1-methyl-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1,2,3,6-tetrahydropyridine (from Aldrich, 250 mg, 1.12 mmol), A mixture of potassium phosphate (0.61 g, 2.9 mmol) in 1,4-dioxane (3.4 mL) and water (1.1 mL) was degassed, refilled with nitrogen, and dicyclohexyl (2',4', 6'-Triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (110 mg, 0.14 mmol). The reaction mixture was degassed again, refilled with nitrogen and then sealed and heated at 80 °C for 1 h. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give crude product, which was used directly in the next step. LCMS calculated value for C ₁₂ H ₁₆ N ₅ (M+H) ⁺ : m/z = 230.1. Experimental value: 230.1. Step 2 : 7-(1- methylpiperidin- 4- yl ) pyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (134 mg To a solution of , 0.26 mmol) in methanol (1.26 mL) and THF (0.5 mL) was added a palladium mixture (150 mg, 0.14 mmol) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 4 hours. After filtration through a pad of celite, the filtrate was concentrated under vacuum to yield crude material. The crude material was resolved by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) Further purification yielded the desired product as a white powder (22 mg, 36%). LCMS calculated value for C ₁₂ H ₁₈ N ₅ (M+H) ⁺ : m/z = 232.2. Experimental value: 232.2. Step 3 : 5- bromo -7-(1- methylpiperidin- 4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 4- amine

To 7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (16.5 mg, 0.07 mmol) in N,N -bis To a solution of methylformamide (0.31 mL) and tetrahydrofuran (0.20 mL) was added N -bromosuccinimide (10.2 mg, 0.06 mmol). The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered and concentrated under vacuum to give the desired product as a tan solid. LCMS calculated value for C ₁₂ H ₁₇ BrN ₅ (M+H) ⁺ : m/z = 310.1, 312.1. Experimental values: 310.1, 312.1. Step 4 : N-{4-[4- amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (4 mg , 0.013 mmol), 2-side oxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl) Phenyl]-1,2-dihydropyridine-3-carboxamide (5.6 mg, 0.014 mmol) (prepared in Example 7, Step 3) and N,N -diisopropylethylamine (0.012 mL, 0.078 mmol) was stirred together in 1,4-dioxane (0.15 m) and water (20 μL) and flushed with N for 5 min, after which _bis (tri-tert-butylphosphine)palladium (3.3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (4.0 mg, 60%). LCMS calculated for C ₃₀ H ₃₀ N ₇ O ₂ (M+H) ⁺ : m/z = 520.2. Experimental value: 520.2. Example 21. N -{4-[4- Amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (4 mg , 0.013 mmol) (prepared in Example 20, step 3), 1-(4-fluorophenyl)-2-pendantoxy- N- [4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (5.9 mg, 0.014 mmol) (prepared in Example 9, step 3) and A mixture of N,N -diisopropylethylamine (0.014 mL, 0.04 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with N for ₅ min before adding Bis(tri-tert-butylphosphine)palladium (3.3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.1 mg, 30%). LCMS calculated for C ₃₀ H ₂₉ FN ₇ O ₂ (M+H) ⁺ : m/z = 538.2. Experimental value: 538.2. Example 22. N -{4-[4- amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3- fluorophenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (3 mg , 0.01 mmol) (prepared in Example 20, step 3), N -[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2 -yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (4.2 mg, 0.01 mmol) (prepared in Example 9, step 4) and N , a mixture of N -diisopropylethylamine (0.01 mL, 0.03 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N for 5 min, after which dihydrogen was added. (Tri-tert-butylphosphine)palladium (2.5 mg, 0.005 mmol). The reaction mixture was sealed and then heated at 110°C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield desired product. LCMS calculated for C ₃₀ H ₂₉ FN ₇ O ₂ (M+H) ⁺ : m/z = 538.2. Experimental value: 538.2. Example 23. N -{4-[4- Amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3- Fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (4 mg , 0.013 mmol) (prepared in Example 20, step 3), 1-(4-fluorophenyl) -N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-methamide (5.8 mg, 0.013 mmol) (in Example 9, Step 5 A mixture of N, N -diisopropylethylamine (0.014 mL, 0.08 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N2 for 5 min before adding bis(tri-tert-butylphosphine)palladium (3.3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.5 mg, 35%). LCMS calculated for C ₃₀ H ₂₈ F ₂ N ₇ O ₂ (M+H) ⁺ : m/z = 556.3. Experimental value: 556.3. Example 24. N -{4-[7-(1- acetylpiperidin- 4- yl )-4- aminopyrrolo [2,1- f ][1,2,4] triazine -5- base ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 7-(1- acetyl -1,2,3,6- tetrahydropyridin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 4- amine

1-Acetyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1,2,3,6-tetrahydropyridine (from Combi-Blocks, 500 mg, 1.99 mmol), 7-bromopyrrolo[2,1 -f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 424 mg, 1.99 mmol), sodium carbonate (700 mg, 6.6 mmol) and [1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (199 mg, 0.26 mmol) in tert-butanol (6.0 mL) and water (2.2 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h. The mixture was diluted with ethyl acetate, washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and _concentrated . The product was purified by Biotage silica gel chromatography (20 g column, 0 to 30% MeOH in EtOAc) to yield the desired product as a brown solid (317 mg, 62%). LCMS calculated value for C ₁₃ H ₁₆ N ₅ O (M+H) ⁺ : m/z = 258.1. Experimental value: 258.1. Step 2 : 7-(1- acetylpiperidin- 4- yl ) pyrrolo [2,1-f][1,2,4] triazin -4- amine

To 7-(1-acetyl-1,2,3,6-tetrahydropyridin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (305 mg, 1.19 mmol) to a turbid solution in methanol (4.9 mL) and tetrahydrofuran (2.4 mL) was added a palladium mixture (610 mg) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 18 h and filtered through a pad of celite. The filtrate was concentrated under vacuum to yield the desired product as a light brown powder (187 mg, 61%). LCMS calculated value for C ₁₃ H ₁₈ N ₅ O (M+H) ⁺ : m/z = 260.1. Experimental value: 260.1. Step 3 : 7-(1- acetylpiperidin- 4- yl )-5- bromopyrrolo [2,1-f][1,2,4] triazin- 4- amine

To 7-(1-ethylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (178 mg, 0.69 mmol) in N,N - To a solution in dimethylformamide (3.0 mL) was added N -bromosuccinimide (116 mg, 0.65 mmol). The resulting mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered and concentrated under vacuum to give the desired product as a tan solid. LCMS calculated value for C ₁₃ H ₁₇ BrN ₅ O (M+H) ⁺ : m/z = 338.1, 340.1. Experimental values: 338.1, 340.1. Step 4 : N-{4-[7-(1- acetylpiperidin- 4- yl )-4- aminopyrrolo [2,1-f][1,2,4] triazine -5- base ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 7-(1-ethylpiperidin-4-yl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (6 mg, 0.02 mmol), 2-side oxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl )phenyl]-1,2-dihydropyridine-3-carboxamide (7.8 mg, 0.019 mmol) (prepared in Example 7, Step 3) and N,N -diisopropylethylamine (0.018 mL, A mixture of 0.11 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with N for 5 min, after which _bis (tri-tert-butylphosphine)palladium (4.5 mg, 0.009 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (3.0 mg, 31%). LCMS calculated for C ₃₁ H ₃₀ N ₇ O ₃ (M+H) ⁺ : m/z = 548.2. Experimental value: 548.2. Example 25. N -{4-[7-(1- acetylpiperidin- 4- yl )-4- aminopyrrolo [2,1- f ][1,2,4] triazine -5- [base ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 7-(1-ethylpiperidin-4-yl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), 1-(4-fluorophenyl)-2-pendantoxy- N -[4-(4,4,5,5-tetramethyl- 1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (8.1 mg, 0.019 mmol) (prepared in Example 9, step 3) A mixture of N,N -diisopropylethylamine (0.018 mL, 0.11 mmol) was stirred in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N for 5 min. Bis(tri-tert-butylphosphine)palladium (4.5 mg, 0.009 mmol) was added. The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.9 mg, 29%). LCMS calculated for C ₃₁ H ₂₉ FN ₇ O ₃ (M+H) ⁺ : m/z = 566.2. Experimental value: 566.2. Example 26. N- {4-[7-(1- acetylpiperidin- 4- yl )-4- aminopyrrolo [2,1 -f ][1,2,4] triazine -5- base ]-3- fluorophenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 7-(1-ethylpiperidin-4-yl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), N -[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane- 2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (8.1 mg, 0.02 mmol) (prepared in Example 9, step 4) and A mixture of N,N -diisopropylethylamine (0.18 mL, 0.11 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with N for ₅ min before adding Bis(tri-tert-butylphosphine)palladium (4.5 mg, 0.01 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.4 mg, 24%). LCMS calculated for C ₃₁ H ₂₉ FN ₇ O ₃ (M+H) ⁺ : m/z = 566.2. Experimental value: 566.2. Example 27. N -{4-[7-(1- acetylpiperidin- 4- yl )-4- aminopyrrolo [2,1- f ][1,2,4] triazine -5- base ]-3- fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 7-(1-ethylpiperidin-4-yl)-5-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (6 mg, 0.02 mmol) (prepared in Example 24, step 3), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-methamide (8.4 mg, 0.02 mmol) (in Example 9, step A mixture of (prepared in 5) and N,N -diisopropylethylamine (0.018 mL, 0.11 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N 5 min before adding bis(tri-tert-butylphosphine)palladium (4.5 mg, 0.009 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to yield the desired product (2.3 mg, 22%) as a milky white powder. LCMS calculated for C ₃₁ H ₂₈ F ₂ N ₇ O ₃ (M+H) ⁺ : m/z = 584.2. Experimental value: 584.2. Example 28a. N -{4-[4- Amino- 7-( cis -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] benzene Example 28b . N - {4-[4 - amino - 7- ( trans - 4 - cyano ) Cyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-2- side oxy -1- phenyl -1,2- dihydropyridine -3 -Formamide _ Step 1 : 4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohex - 3- ene -1- carbonitrile

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-ene-1-carbonitrile (from Pharma Block, 500 mg , 2.15 mmol), 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 457 mg, 2.14 mmol), sodium carbonate (760 mg , 7.1 mmol) and [1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (211 mg, 0.279 mmol) in tert-butanol (6.4 mL) and water (2.4 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h. The mixture was diluted with ethyl acetate, washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and _concentrated . The product was purified by Biotage silica gel chromatography (20 g column, 0 to 100% EtOAc in hexanes) to yield the desired product (238 mg, 46%) as a creamy white powder. LCMS calculated for C ₁₃ H ₁₄ N ₅ (M+H) ⁺ : m/z = 240.1. Experimental value: 240.1. Step 2 : 4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohexanecarbonitrile

To 4-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohex-3-ene-1-carbonitrile (238 mg, 0.99 mmol) in To a solution in methanol (4.1 mL) and tetrahydrofuran (2.0 mL) was added the palladium mixture (512 mg) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 18 h. After filtration through a pad of celite, the filtrate was concentrated under vacuum to yield the desired product as a clear gum (147.2 mg, 61%). LCMS calculated value for C ₁₃ H ₁₆ N ₅ (M+H) ⁺ : m/z = 242.1. Experimental value: 242.1. Step 3 : 4-(4- amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohexanecarbonitrile

To 4-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (137 mg, 0.57 mmol) in N,N -dimethyl To a solution of methylformamide (2.4 mL) was added N -bromosuccinimide (96 mg, 0.54 mmol). The resulting mixture was stirred at room temperature for 15 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered and concentrated under vacuum to give the desired product as a creamy white powder (182 mg, 100%). LCMS calculated for C ₁₃ H ₁₅ BrN ₅ (M+H) ⁺ : m/z = 320.0, 322.0. Experimental values: 320.0, 322.0. Step 4 : N-{4-[4- Amino- 7-(4- cyanocyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ] phenyl } -2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (9 mg, 0.03 mmol), 2-side oxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)benzene methyl]-1,2-dihydropyridine-3-carboxamide (11.7 mg, 0.028 mmol) (prepared in Example 7, Step 3) and N,N -diisopropylethylamine (0.015 mL, 0.084 mmol ) was stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and flushed with N for 5 min, then _bis (tri-tert-butylphosphine)palladium (7.2 mg, 0.014 mmol) was added ). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) To produce the desired cis isomer in the form of milky white powder. The RT of the cis isomer is 1.341 min, and it is the first peak leaving the column. LCMS calculated for C ₃₁ H ₂₈ N ₇ O ₂ (M+H) ⁺ : m/z = 530.2. Experimental value: 530.2. Example 29a. N -{4-[4- Amino- 7-( cis -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] benzene Base }-1-(4- fluorophenyl ) -2- side oxy -1,2- dihydropyridine -3 - methamide Example 29b . -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (9 mg, 0.028 mmol) (prepared in Example 28, step 3), 1-(4-fluorophenyl)-2-pendantoxy- N- [4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (13 mg, 0.03 mmol) (prepared in Example 9, step 3) and N , a mixture of N -diisopropylethylamine (0.015 mL, 0.08 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and rinsed with _N for 5 min, then bis (Tri-tert-butylphosphine)palladium (7.2 mg, 0.014 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to produce the desired cis isomer. RT of cis isomer = 1.352 min, the first peak leaving the column. LCMS (M+H)+: found m/z = 548.3. LCMS calculated for C ₃₁ H ₂₇ FN ₇ O ₂ (M+H) ⁺ : m/z = 548.2. Experimental value: 548.2. Example 30a. N -{4-[4- Amino- 7-( cis -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ]- 3- Fluorophenyl }-2- side oxy -1- phenyl - 1,2- dihydropyridine -3- methamide Example 30b. N -{4-[4- amino - 7- ( trans- 4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3- fluorophenyl }-2- side oxy -1- phenyl -1 ,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (9 mg, 0.028 mmol) (prepared in Example 28, step 3), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2- (13 mg, 0.03 mmol) (prepared in Example 9, step 4) and N, A mixture of N -diisopropylethylamine (0.015 mL, 0.084 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and rinsed with N for ₅ min, after which bis( Tributylphosphine)palladium (7.2 mg, 0.014 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to produce the desired cis isomer in the form of a white powder. RT of cis isomer = 1.332 min, the first peak leaving the column. LCMS calculated for C ₃₁ H ₂₇ FN ₇ O ₂ (M+H) ⁺ : m/z = 548.2. Experimental value: 548.2. Example 31a. N -{4-[4- Amino- 7-( cis -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ]- 3- Fluorophenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide Example 31b. N -{4-[4 - amino- 7-( trans -4- cyanocyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ]-3- fluorophenyl }-1-(4- fluorobenzene base )-2- Pendantoxy -1,2- dihydropyridine -3- carboxamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexanecarbonitrile (9 mg, 0.03 mmol) (prepared in Example 28, step 3), 1-(4-fluorophenyl) -N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3, 2-dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-methamide (13 mg, 0.03 mmol) (in Example 9, Step 5 Preparation) and N,N -diisopropylethylamine (0.015 mL, 0.084 mmol) were stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and rinsed with _N bubbles for 5 min before adding bis(tri-tert-butylphosphine)palladium (7.2 mg, 0.014 mmol). The reaction mixture was sealed and then heated at 110 °C for 1 h. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 10 method; XBridge ^™ PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, gradient elution with MeCN and water with 0.15% NH ₄ OH) to produce the desired cis isomer in the form of a white powder. RT of cis isomer = 2.666 min, the first peak leaving the column. LCMS (M+H)+: found m/z = 566.3. LCMS calculated for C ₃₁ H ₂₆ F ₂ N ₇ O ₂ (M+H) ⁺ : m/z = 566.2. Experimental value: 566.2. Example 32. N- [4-(4- amino -7- piperidin- 4- ylpyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl ]-2 -Pendant oxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl )-3,6- dihydropyridine -1(2H) -carboxylic acid tertiary Butyl ester

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)-3,6-dihydropyridine-1(2 H )-carboxylic acid Butyl ester (from Aldrich, 0.885 g, 2.86 mmol), 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (from J & W Pharm Lab, 610 mg, 2.86 mmol), sodium carbonate (1.0 g, 9.5 mmol) and [1,1'-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (217 mg, 0.286 mmol) in tert-butanol (8.6 mL) and water (3.2 mL) was degassed with nitrogen, then stirred and heated at 110 °C for 2 h. The mixture was diluted with ethyl acetate, washed with saturated _NaHCO3 , water, dried over _Na2SO4 , filtered and _concentrated . The crude material was purified by Biotage silica gel chromatography (40 g column, 0 to 100% EtOAc in hexanes) to yield the desired product (705 mg, 78%) as a creamy white powder. LCMS calculated for C ₁₆ H ₂₂ N ₅ O ₂ (M+H) ⁺ : m/z = 316.2. Experimental value: 316.2. Step 2 : 4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylic acid tert-butyl ester

To tert-butyl 4-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)-3,6-dihydropyridine-1(2 H )-carboxylate To a slightly turbid solution of the ester (700 mg, 2.22 mmol) in methanol (9.2 mL) and tetrahydrofuran (4.6 mL) was added a palladium mixture (2.20 g) (10% Pd on carbon). The reaction mixture was placed under a hydrogen balloon for 20 h and filtered through a pad of celite. The filtrate was concentrated under vacuum to yield the desired product as a light brown powder (455 mg, 65%). LCMS calculated for C ₁₆ H ₂₄ N ₅ O ₂ (M+H) ⁺ : m/z = 318.2. Experimental value: 318.2. Step 3 : 4-(4- Amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylic acid tert-butyl ester

To 4-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (450 mg, 1.42 mmol) in N , to a solution of N -dimethylformamide (6.1 mL) was added N -bromosuccinimide (240 mg, 1.35 mmol). The resulting mixture was stirred at room temperature for 10 min. The reaction mixture was diluted with EtOAc and filtered. The filtrate was washed with saturated _NaHCO3 , water, dried, filtered and concentrated under vacuum to give the desired product as a tan solid. LCMS calculated for C ₁₆ H ₂₃ BrN ₅ O ₂ (M+H) ⁺ : m/z = 396.1, 398.1. Experimental values: 396.1, 398.1. Step 4 : 5- Bromo -7- piperidin -4- ylpyrrolo [2,1-f][1,2,4] triazin -4- amine dihydrochloride

4-(4-Amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (562 mg, 1.42 mmol) with methanol (3.5 mL) and 4.0 M hydrochloric acid in dioxane (7.1 mL). The mixture was stirred at room temperature for 1 h. After concentration, the crude product was directly used in the next step in the form of milky white powder. LCMS calculated value for C ₁₁ H ₁₅ BrN ₅ (M+H) ⁺ : m/z = 296.0, 298.0. Experimental values: 296.0, 298.0. Step 5 : N-[4-(4- amino -7- piperidin -4- ylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-2 -Pendant oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-piperidin-4-ylpyrrolo[2,1 -f ][1,2,4]triazin-4-amine dihydrochloride (6.7 mg, 0.013 mmol), 2-side oxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl ]-1,2-dihydropyridine-3-carboxamide (5.4 mg, 0.013 mmol) (prepared in Example 7, step 3) and N,N -diisopropylethylamine (0.013 mL, 0.077 mmol) The mixture was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with N for 5 min, after which _bis (tri-tert-butylphosphine)palladium (3.3 mg, 0.0064 mmol) was added . The reaction mixture was sealed and then heated at 110°C for 60 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was available as a milky white powder (4 mg, 61%). LCMS calculated for C ₂₉ H ₂₈ N ₇ O ₂ (M+H) ⁺ : m/z = 506.2. Experimental value: 506.2. Example 33. N- [4-(4- amino -7- piperidin- 4- ylpyrrolo [2,1 -f ][1,2,4] triazin -5- yl ) phenyl ]-1 -(4- Fluorophenyl )-2- Pendantoxy -1,2- dihydropyridine -3- carboxamide

In a sealed tube, 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), 1-(4-fluorophenyl)-2-pendantoxy- N -[4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (5.6 mg, 0.013 mmol) (prepared in Example 9, step 3) and N, A mixture of N -diisopropylethylamine (0.013 mL, 0.08 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N for 5 min, after which bis( Tributylphosphine)palladium (3.3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110°C for 60 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (4 mg, 59%). LCMS calculated for C ₂₉ H ₂₇ FN ₇ O ₂ (M+H) ⁺ : m/z = 524.2. Experimental value: 524.2. Example 34. N -[4-(4- Amino -7- piperidin- 4- ylpyrrolo [2,1- f ][1,2,4] triazin -5- yl )-3- fluorobenzene base ]-2- Pendant oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl )phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (5.6 mg, 0.013 mmol) (prepared in Example 9, step 4) and N,N - A mixture of diisopropylethylamine (0.0067 mL, 0.039 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with _N for 5 min before adding bis(tris) tert-Butylphosphine)palladium (3.3 mg, 0.006 mmol). The reaction mixture was sealed and then heated at 110°C for 60 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a milky white powder (3.2 mg, 47%). LCMS calculated for C ₂₉ H ₂₇ FN ₇ O ₂ (M+H) ⁺ : m/z = 524.2. Experimental value: 524.2. Example 35. N -[4-(4- Amino -7- piperidin- 4- ylpyrrolo [2,1- f ][1,2,4] triazin -5- yl )-3- fluorobenzene base ]-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (6.7 mg, 0.013 mmol) (prepared in Example 32, step 4), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2 -Dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-methamide (5.8 mg, 0.013 mmol) (prepared in Example 9, Step 5 ) and N,N -diisopropylethylamine (0.014 mL, 0.077 mmol) were stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with N for ₅ min. Bis(tri-tert-butylphosphine)palladium (3.3 mg, 0.006 mmol) was then added. The reaction mixture was sealed and then heated at 110°C for 60 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (3.6 mg, 52%). LCMS calculated for C ₂₉ H ₂₆ F ₂ N ₇ O ₂ (M+H) ⁺ : m/z = 542.2. Experimental value: 542.2. Example 36. 4-[4- Amino- 5-(4-{[(2 -Pendantoxy -1- phenyl -1,2- dihydropyridin -3- yl ) carbonyl ] amino } phenyl ) Methyl pyrrolo [2,1- f ][1,2,4] triazin -7- yl ] piperidine -1- carboxylate Step 1 : Methyl 4-(4- amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylate

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (56 mg, 0.11 mmol) (in Example 32 , prepared in step 4), to the mixture in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (0.65 mL, 0.65 mmol), and then methyl chloroformate (42 μL, 0.54 mmol) was slowly added at 0°C. . After stirring at room temperature for 10 min, the resulting mixture was filtered, extracted with EtOAc, dried, filtered and concentrated under reduced pressure to dryness. The crude material obtained was used directly in the next step as a pale yellow powder (52.6 mg). LCMS calculated for C ₁₃ H ₁₇ BrN ₅ O ₂ (M+H) ⁺ : m/z = 354.0, 356.0. Experimental values: 354.0, 356.0. Step 2 : 4-[4- amino- 5-(4-{[(2- side oxy -1- phenyl -1,2- dihydropyridin -3- yl ) carbonyl ] amino } phenyl ) Methyl pyrrolo [2,1-f][1,2,4] triazin -7- yl ] piperidine -1- carboxylate

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid methyl ester ( 6.8 mg, 0.014 mmol), 2-Pendantoxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane-2- phenyl]-1,2-dihydropyridine-3-carboxamide (6.2 mg, 0.015 mmol) (prepared in Example 7, step 3) and N,N -diisopropylethylamine (0.0074 mL , 0.042 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and flushed with N for 5 min, after which _bis (tri-tert-butylphosphine)palladium (3.6 mg ,0.007 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was available as a milky white powder (6.5 mg, 82%). LCMS calculated for C ₃₁ H ₃₀ N ₇ O ₄ (M+H) ⁺ : m/z = 564.2. Experimental value: 564.2. Example 37. 4-{4- Amino -5-[4-({[1-(4- fluorophenyl )-2- pendantoxy -1,2- dihydropyridin -3- yl ] carbonyl } amine methyl ) phenyl ] pyrrolo [2,1- f ][1,2,4] triazin -7- yl } piperidine -1- carboxylate

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid methyl ester ( 6.8 mg, 0.014 mmol) (prepared in Example 36, step 1), 1-(4-fluorophenyl)-2-pendantoxy- N -[4-(4,4,5,5-tetramethyl -1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (6.4 mg, 0.015 mmol) (prepared in Example 9, step 3 ) and N,N -diisopropylethylamine (0.0074 mL, 0.042 mmol) were stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and flushed with N for ₅ min. Bis(tri-tert-butylphosphine)palladium (3.6 mg, 0.007 mmol) was then added. The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product (5.0 mg, 61%) as a milky white powder. LC-MS experimental value m/z = 582.3. LCMS calculated for C ₃₁ H ₂₉ FN ₇ O ₄ (M+H) ⁺ : m/z = 582.2. Experimental value: 582.2. Example 38. 4-[4- Amino- 5-(2- fluoro -4-{[(2- Pendantoxy -1- phenyl -1,2- dihydropyridin -3- yl ) carbonyl ] amine } Phenyl ) pyrrolo [2,1- f ][1,2,4] triazin- 7- yl ] piperidine -1- carboxylic acid methyl ester

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid methyl ester ( 6.8 mg, 0.014 mmol) (prepared in Example 36, step 1), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane) -2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (6.4 mg, 0.015 mmol) (prepared in Example 9, step 4) and N,N -diisopropylethylamine (0.0074 mL, 0.04 mmol) were stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) and rinsed with N for ₅ min, then Bis(tri-tert-butylphosphine)palladium (3.6 mg, 0.007 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (6.4 mg, 78%). LCMS calculated for C ₃₁ H ₂₉ FN ₇ O ₄ (M+H) ⁺ : m/z = 582.2. Experimental value: 582.2. Example 39. 4-{4- Amino -5-[2- fluoro -4-({[1-(4- fluorophenyl )-2- pendantoxy -1,2- dihydropyridin -3- yl ] carbonyl } amino ) phenyl ] pyrrolo [2,1- f ][1,2,4] triazin -7- yl } piperidine -1- carboxylic acid methyl ester

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid methyl ester ( 6.8 mg, 0.014 mmol) (prepared in Example 36, step 1), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1,2-dihydropyridine-3-methamide (6.7 mg, 0.015 mmol) (in Example 9, A mixture of (prepared in step 5) and N,N -diisopropylethylamine (0.0074 mL, 0.042 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (20 μL) with _N2 Rinse for 5 min before adding bis(tri-tert-butylphosphine)palladium (3.6 mg, 0.007 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (4.9 mg, 58%). LCMS calculated for C ₃₁ H ₂₈ F ₂ N ₇ O ₄ (M+H) ⁺ : m/z = 600.2. Experimental value: 600.2. Example 40. N -(4-{4- amino -7-[1-( methylsulfonyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tri Azin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide Step 1 : 5- bromo -7-[1-( methylsulfonyl ) piperidin - 4- yl ] pyrrolo [2,1-f][1,2,4] triazin- 4- amine

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (56 mg, 0.11 mmol) (in Example 32 , prepared in step 4) to the mixture in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (0.65 mL), followed by methanesulfonyl chloride (13 μL, 0.16 mmol) slowly added at 0°C. After stirring at room temperature for 10 min, the resulting mixture was filtered, extracted with EtOAc, dried, filtered and concentrated under reduced pressure to dryness. The crude material obtained was used directly in the next step as a pale yellow powder (36.5 mg, 90%). LCMS calculated value for C ₁₂ H ₁₇ BrN ₅ O ₂ S (M+H) ⁺ : m/z = 374.0, 376.0. Experimental values: 374.0, 376.0. Step 2 : N-(4-{4- amino- 7-[1-( methylsulfonyl ) piperidin -4- yl ] pyrrolo [2,1-f][1,2,4] tri Azin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide

In a sealed tube, 5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine-4 -Amine (5 mg, 0.01 mmol), 2-Pendantoxy-1-phenyl- N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane -2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (5.8 mg, 0.014 mmol) (prepared in Example 7, Step 3) and N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine)palladium (3.4 mg, 0.0067 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (5.4 mg, 69%). LCMS calculated value for C ₃₀ H ₃₀ N ₇ O ₄ S (M+H) ⁺ : m/z = 584.2. Experimental value: 584.2. Example 41. N- (4-{4- amino -7-[1-( methylsulfonyl ) piperidin -4- yl ] pyrrolo [2,1 -f ][1,2,4] tri Azin -5- yl } phenyl )-1-(4- fluorophenyl )-2- side-oxy -1,2- dihydropyridin -3- methamide

In a sealed tube, 5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine-4 -Amine (5 mg, 0.013 mmol) (prepared in Example 40, Step 1), 1-(4-fluorophenyl)-2-pendantoxy-N-[4-(4,4,5,5- Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (6.1 mg, 0.014 mmol) (in Example 9, step A mixture of (prepared in 3) and N,N -diisopropylethylamine (0.01 mL, 0.06 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and rinsed with _N 5 min before adding bis(tri-tert-butylphosphine)palladium (3.4 mg, 0.0067 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (6.2 mg, 77%). LCMS calculated value for C ₃₀ H ₂₉ FN ₇ O ₄ S (M+H) ⁺ : m/z = 602.2. Experimental value: 602.2. Example 42. N- (4-{4- amino -7-[1-( methylsulfonyl ) piperidin -4- yl ] pyrrolo [2,1 -f ][1,2,4] tri Azin -5- yl }-3- fluorophenyl )-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine-4 -Amine (5 mg, 0.013 mmol) (prepared in Example 40, step 1), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boronpentan-2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide (6.1 mg, 0.014 mmol) (in Example 9, Step 4 A mixture of N, N -diisopropylethylamine (0.01 mL, 0.06 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL) and flushed with _N2 for 5 min before adding bis(tri-tert-butylphosphine)palladium (3.4 mg, 0.0067 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (3.8 mg, 47%). LCMS calculated value for C ₃₀ H ₂₉ FN ₇ O ₄ S (M+H) ⁺ : m/z = 602.2. Experimental value: 602.2. Example 43. N- (4-{4- amino -7-[1-( methylsulfonyl ) piperidin -4- yl ] pyrrolo [2,1 -f ][1,2,4] tri Azin -5- yl }-3- fluorophenyl )-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-[1-(methylsulfonyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine-4 -Amine (5.3 mg, 0.014 mmol) (prepared in Example 40, step 1), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl (1,3,2-dioxaboropentan-2-yl)phenyl]-2-pentanoxy-1,2-dihydropyridine-3-methamide (6.7 mg, 0.015 mmol) (in A mixture of Example 9, prepared in step 5) and N,N -diisopropylethylamine (0.01 mL, 0.05 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (20 μL). Flush with _N for 5 min before adding bis(tri-tert-butylphosphine)palladium (3.6 mg, 0.007 mmol). The reaction mixture was sealed and then heated at 110°C for 30 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (3.2 mg, 36%). LCMS calculated value for C ₃₀ H ₂₈ F ₂ N ₇ O ₄ S (M+H) ⁺ : m/z = 620.2. Experimental value: 620.2. Example 44. N -[4-(4- Amino- 7-{1-[( dimethylamino ) carbonyl ] piperidin- 4- yl } pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl ) phenyl ]-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide Step 1 : 4-(4- Amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl )-N,N -dimethylpiperidine -1- Formamide

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (56 mg, 0.11 mmol) (in Example 32 , prepared in step 4), to the mixture in tetrahydrofuran (0.6 mL) was added 1.0 M sodium bicarbonate in water (0.65 mL, 0.65 mmol), and then N,N -dimethylaminoformate chloride was slowly added at 0°C. (140 mg, 1.3 mmol). After stirring at room temperature for 80 min, the resulting mixture was filtered, extracted with EtOAc, dried, filtered and concentrated under reduced pressure to dryness. The crude material obtained was used directly in the next step as a pale yellow powder (59.8 mg). LCMS calculated value for C ₁₄ H ₂₀ BrN ₆ O (M+H) ⁺ : m/z = 367.1, 369.1. Experimental values: 367.1, 369.1. Step 2 : N-[4-(4- amino -7-{1-[( dimethylamino ) carbonyl ] piperidin -4- yl } pyrrolo [2,1-f][1,2,4 ] triazin -5- yl ) phenyl ]-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N,N -dimethylpiper 1-Methodamide (3.8 mg, 0.007 mmol), 2-Pendantoxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (3.1 mg, 0.0074 mmol) (prepared in Example 7, step 3) and N,N-dihydropyridine -3-carboxamide (3.1 mg, 0.0074 mmol) A mixture of isopropylethylamine (0.004 mL, 0.02 mmol) was stirred together in 1,4-dioxane (0.1 mL) and water (15 μL) and flushed with _N for 5 min, after which bis(tristriol) was added. Butylphosphine)palladium (1.8 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 50 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (2 mg, 49%). LCMS calculated for C ₃₂ H ₃₃ N ₈ O ₃ (M+H) ⁺ : m/z = 577.3. Experimental value: 577.3. Example 45. N -[4-(4- Amino- 7-{1-[( dimethylamino ) carbonyl ] piperidin- 4- yl } pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl ) phenyl ]-1-(4- fluorophenyl )-2- pendantoxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N,N -dimethylpiper 1-(4-Fluorophenyl)-2-Pendantoxy- N -[4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (3.2 mg, 0.0074 mmol)( A mixture of (prepared in Example 9, Step 3) and N,N -diisopropylethylamine (0.006 mL, 0.03 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (10 μL). and _flushed with N for 5 min, after which bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (2.3 mg, 55%). LCMS calculated for C ₃₂ H ₃₂ FN ₈ O ₃ (M+H) ⁺ : m/z = 595.3. Experimental value: 595.3. Example 46. N -[4-(4- Amino- 7-{1-[( dimethylamino ) carbonyl ] piperidin- 4- yl } pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl )-3- fluorophenyl ]-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N,N -dimethylpiper D- [3-Fluoro-4-(4,4,5,5-tetramethyl-1,3) (3.8 mg, 0.007 mmol) (prepared in Example 44, Step 1), ,2-dioxaboropentan-2-yl)phenyl]-2-side oxy-1-phenyl-1,2-dihydropyridine-3-methamide (3.2 mg, 0.0074 mmol) (in A mixture of Example 9, prepared in step 4) and N,N -diisopropylethylamine (0.006 mL, 0.03 mmol) was stirred together in 1,4-dioxane (0.11 mL) and water (10 μL). Flush with _N for 5 min before adding bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (3.8 mg, 91%). LCMS calculated for C ₃₂ H ₃₂ FN ₈ O ₃ (M+H) ⁺ : m/z = 595.3. Experimental value: 595.3. Example 47. N -[4-(4- Amino- 7-{1-[( dimethylamino ) carbonyl ] piperidin- 4- yl } pyrrolo [2,1- f ][1,2,4 ] Triazin -5- yl )-3- fluorophenyl ]-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N,N -dimethylpiper 1-(4-fluorophenyl) -N- [3-fluoro-4-(4,4,5) (prepared in Example 44, step 1) ,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2-side oxy-1,2-dihydropyridine-3-methamide (3.3 mg, A mixture of 0.0074 mmol) (prepared in Example 9, Step 5) and N,N -diisopropylethylamine (0.006 mL, 0.03 mmol) in 1,4-dioxane (0.11 mL) and water (15 μL ) and flushed with _N for 5 min, after which bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (2.4 mg, 56%). LCMS calculated for C ₃₂ H ₃₁ F ₂ N ₈ O ₃ (M+H) ⁺ : m/z = 613.2. Experimental value: 613.2. Example 48. N -(4-{4- amino -7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide Step 1 : 5- bromo -7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1-f][1,2,4] triazin- 4- amine

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1 -f ][1,2,4]triazin-4-amine dihydrochloride (56 mg, 0.11 mmol) (in Example 32 , prepared in step 4) To the mixture in ethanol (0.5 mL), add potassium carbonate (90 mg, 0.65 mmol), triethylamine (91 μL, 0.65 mmol) and potassium iodide (27 mg, 0.16 mmol), followed by 1 -Bromo-2-methoxyethane (75.4 mg, 0.54 mmol). The reaction mixture was sealed and refluxed in a 110 °C oil bath for 1 h. After cooling, the mixture was filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to yield the desired product as a milky white powder. LCMS calculated value for C ₁₄ H ₂₁ BrN ₅ O (M+H) ⁺ : m/z = 354.1, 356.1. Experimental values: 354.1, 356.1. Step 2 : N-(4-{4- amino- 7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1-f][1,2,4 ] triazin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide

In a sealed tube, 5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine -4-amine (7.6 mg, 0.01 mmol), 2-side oxy-1-phenyl- N -[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Pentan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (3.7 mg, 0.01 mmol) (prepared in Example 7, step 3) and N,N -diisopropyl A mixture of ethylamine (0.006 mL, 0.03 mmol) was stirred together in 1,4-dioxane (0.1 mL) and water (10 μL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine) )palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (4 mg, 84%). LCMS calculated for C ₃₂ H ₃₄ N ₇ O ₃ (M+H) ⁺ : m/z = 564.3. Experimental value: 564.3. Example 49. N -(4-{4- amino -7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl } phenyl )-1-(4- fluorophenyl )-2- pendantoxy -1,2- dihydropyridin -3- methamide

In a sealed tube, 5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine -4-amine (7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1), 1-(4-fluorophenyl)-2-side oxy- N- [4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (3.9 mg, 0.01 mmol) (in Example 9 , prepared in step 3) and N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) were stirred together in 1,4-dioxane (0.1 mL) and water (10 μL) and mixed with N ₂ Rinse for 5 min, then add bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was available as a milky white powder (3.2 mg, 65%). LCMS calculated for C ₃₂ H ₃₃ FN ₇ O ₃ (M+H) ⁺ : m/z = 582.3. Experimental value: 582.3. Example 50. N -(4-{4- amino -7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4 ] triazin -5- yl }-3- fluorophenyl )-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine -4-amine (7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1), N- [3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboropentan-2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide (3.9 mg, 0.01 mmol) (in Example 9, A mixture of (prepared in step 4) and N,N -diisopropylethylamine (0.007 mL, 0.03 mmol) was stirred together in 1,4-dioxane (0.12 mL) and water (15 μL) with _N2 Rinse for 5 min before adding bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a milky white powder (3.9 mg, 79%). LCMS calculated for C ₃₂ H ₃₃ FN ₇ O ₃ (M+H) ⁺ : m/z = 582.3. Experimental value: 582.3. Example 51. N -(4-{4- amino -7-[1-(2- methoxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4 ] Triazin -5- yl }-3- fluorophenyl )-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 5-bromo-7-[1-(2-methoxyethyl)piperidin-4-yl]pyrrolo[2,1- f ][1,2,4]triazine -4-amine (7.6 mg, 0.0085 mmol) (prepared in Example 48, step 1), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5- Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2-sideoxy-1,2-dihydropyridine-3-methamide (4.0 mg, 0.01 mmol) A mixture of (prepared in Example 9, step 5) and N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL) and water (15 μL) Stir and _flush with N for 5 min before adding bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110 °C for 40 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a white powder (3.5 mg, 69%). LCMS calculated for C ₃₂ H ₃₂ F ₂ N ₇ O ₃ (M+H) ⁺ : m/z = 600.3. Experimental value: 600.3. Example 52. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tri Azin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide Step 1 : 2-[4-(4- Amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl ) piperidin -1- yl ] ethanol

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (56 mg, 0.11 mmol) in ethanol (0.5 mL) (prepared in Example 32, Step 4) were added potassium carbonate (90 mg, 0.65 mmol), triethylamine (91 μL, 0.65 mmol), and potassium iodide (27 mg, 0.16 mmol), followed by 2 -Bromoethanol (67.8 mg, 0.54 mmol). The reaction mixture was sealed and refluxed in a 110 °C oil bath for 1 h. After cooling, the mixture was filtered and the filter cake was washed with THF and EtOH. The filtrate was concentrated under reduced pressure to yield the desired product as a milky white powder. LCMS calculated value for C ₁₂ H ₁₉ BrN ₅ O (M+H) ⁺ : m/z = 340.1, 342.1. Experimental values: 340.1, 342.1. Step 2 : N-(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1-f][1,2,4] tri Azin -5- yl } phenyl )-2- side oxy -1- phenyl -1,2- dihydropyridin -3- methamide

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl ]Ethanol (13 mg, 0.009 mmol), 2-Pendantoxy-1-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane -2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (3.7 mg, 0.01 mmol) (prepared in Example 7, Step 3) and N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (15 μL) and flushed with N for 5 min before adding _bis (tri-tert-butylphosphine)palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 20 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a milky white powder (2.3 mg, 49%). LCMS calculated for C ₃₁ H ₃₂ N ₇ O ₃ (M+H) ⁺ : m/z = 550.3. Experimental value: 550.3. Example 53. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tris Azin -5- yl } phenyl )-1-(4- fluorophenyl )-2- side-oxy -1,2- dihydropyridin -3- methamide

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl ]Ethanol (13 mg, 0.009 mmol) (prepared in Example 52, Step 1), 1-(4-fluorophenyl)-2-pendantoxy- N -[4-(4,4,5,5- Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (3.9 mg, 0.01 mmol) (in Example 9, step A mixture of (prepared in 3) and N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (15 μL) and rinsed with _N 5 min before adding bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.0042 mmol). The reaction mixture was sealed and then heated at 110°C for 20 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a milky white powder (2.3 mg, 48%). LCMS calculated for C ₃₁ H ₃₁ FN ₇ O ₃ (M+H) ⁺ : m/z = 568.2. Experimental value: 568.2. Example 54. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tris Azin -5- yl }-3- fluorophenyl )-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl ] Ethanol (13 mg, 0.009 mmol) (prepared in Example 52, Step 1), N -[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxo Boronpentan-2-yl)phenyl]-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide (3.9 mg, 0.01 mmol) (in Example 9, Step 4 A mixture of N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) was stirred together in 1,4-dioxane (0.15 mL) and water (15 μL) and rinsed with _N2 for 5 min before adding bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.0042 mmol). The reaction mixture was sealed and then heated at 110°C for 20 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was available as a milky white powder (2.7 mg, 56%). LCMS calculated for C ₃₁ H ₃₁ FN ₇ O ₃ (M+H) ⁺ : m/z = 568.2. Experimental value: 568.2. Example 55. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tri Azin -5- yl }-3- fluorophenyl )-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1 -f ][1,2,4]triazin-7-yl)piperidin-1-yl ] ethanol (13 mg, 0.009 mmol) (prepared in Example 52, step 1), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl (1,3,2-dioxaboropentan-2-yl)phenyl]-2-pentanoxy-1,2-dihydropyridine-3-methamide (4.0 mg, 0.01 mmol) (in Example 9, prepared in step 5) and N,N -diisopropylethylamine (0.007 mL, 0.04 mmol) were stirred together in 1,4-dioxane (0.15 mL) and water (15 μL). Flush with _N for 5 min before adding bis(tri-tert-butylphosphine)palladium (2.2 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 20 min. After separation and extraction of the aqueous layer with EtOAc, the organic layer was dried, filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^TM column, 30 × 100 mm, 60 mL/min, gradient elution with MeCN and water with 0.1% TFA) to yield The desired product was obtained as a milky white powder (2.2 mg, 44%). LCMS calculated for C ₃₁ H ₃₀ F ₂ N ₇ O ₃ (M+H) ⁺ : m/z = 586.2. Experimental value: 586.2. Example 56. N -{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1- f ][1 ,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide Step 1 : 4-(4- Amino -5- bromopyrrolo [2,1-f][1,2,4] triazin - 7- yl ) -N- ethyl -N- methylpiperidine- 1- methamide

To 5-bromo-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-4-amine dihydrochloride (20 mg, 0.04 mmol) (in Example 32 , prepared in step 4), to the mixture in tetrahydrofuran (0.2 mL) was added 1.0 M sodium bicarbonate in water (0.23 mL, 0.23 mmol), and then ethyl(methyl)amine methyl chloride (0.23 mL, 0.23 mmol) was slowly added at 0°C. 56.5 mg, 0.46 mmol). After stirring at room temperature for 15 min, the resulting mixture was filtered, extracted with EtOAc, dried, filtered and concentrated under reduced pressure to dryness. The crude material obtained was used directly in the next step as a milky white powder (18.1 mg). LCMS calculated value for C ₁₅ H ₂₂ BrN ₆ O (M+H)+: m/z = 381.1, 383.1. Experimental values: 381.0, 383.0. Step 2 : N-{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2- side oxy -1,2- dihydropyridine -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N -ethyl- N -methyl Piperidin-1-methamide (3.3 mg, 0.007 mmol), 1-(4-fluorophenyl)-2-side oxy- N- [4-(4,4,5,5-tetramethyl -1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (3.2 mg, 0.007 mmol) (prepared in Example 9, step 3 ) and N , N -diisopropylethylamine (0.004 mL, 0.02 mmol) were stirred together in 1,4-dioxane (0.1 mL) and water (14 μL), and then bis(tritriethylamine) was added. Butylphosphine)palladium (1.8 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (2.9 mg, 68%). LCMS calculated for C ₃₃ H ₃₄ FN ₈ O ₃ (M+H)+: m/z = 609.3. Experimental value: 609.3. Example 57. N -{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1- f ][1 ,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquin Phylline -3- methamide Step 1 : 1-(4- Fluorophenyl )-2,5- bisoxy -N-[4-(4,4,5,5 -tetramethyl -1,3,2- dioxaboropentane) Alk -2- yl ) phenyl ]-1,2,5,6,7,8- hexahydroquinoline -3- methamide

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (76.4 mg, 0.35 mmol) and 1-(4-fluorophenyl) -2,5-Dimensyloxy-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (100.0 mg, 0.33 mmol) (prepared in Example 1, step 4) in N , To a mixture of N -dimethylformamide (1.5 mL) was added triethylamine (69 μL, 0.5 mmol), followed by N , N , N ', N '-tetramethyl- O -(7-nitrogen Heterobenzotriazol-1-yl)ureonium hexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture, which quickly became a solid mixture, was stirred at room temperature for 60 min. The precipitate was filtered and washed with water and dried under vacuum to provide the desired product as a white powder (186 mg). LCMS calculated for C ₂₈ H ₂₉ BFN ₂ O ₅ (M+H)+: m/z = 503.1. Experimental value: 503.1. Step 2 : N-{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ] phenyl }-1-(4- fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquin Phylline -3- methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N -ethyl- N -methyl Piperidin-1-carboxamide (3.3 mg, 0.007 mmol) (prepared in Example 56, step 1), 1-(4-fluorophenyl)-2,5-bisoxy- N- [4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2,5,6,7,8-hexahydroquinoline -A mixture of 3-formamide (3.7 mg, 0.007 mmol) and N , N -diisopropylethylamine (0.008 mL, 0.04 mmol) in 1,4-dioxane (0.10 mL) and water (14 μL ), then add bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (3.8 mg, 80%). LCMS calculated for C ₃₇ H ₃₈ FN ₈ O ₄ (M+H)+: m/z = 677.3. Experimental value: 677.3. Example 58. N -{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1- f ][1 ,2,4] triazin -5- yl ]-3- fluorophenyl }-1-(4- fluorophenyl )-2,5- dilateral oxygen -1,2,5,6,7,8 -Hexahydroquinoline -3 - methamide Step 1 : 1-(4- fluorophenyl )-N-[3- fluoro -4-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentan -2- yl ) phenyl ]-2,5- bisoxy -1,2,5,6,7,8- hexahydroquinoline -3- methamide

To 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (82.6 mg, 0.35 mmol) (from Combi-Block) and 1-(4-fluorophenyl)-2,5-bisoxy-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (100.0 mg, 0.33 mmol) (in Examples 1, prepared in step 4) To a mixture of N , N -dimethylformamide (1.5 mL) was added triethylamine (69 μL, 0.5 mmol), followed by N , N , N ', N'- Tetramethyl- O -(7-azabenzotriazol-1-yl)ureonium hexafluorophosphate (151 mg, 0.40 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum to remove most of the solvent and precipitated. The precipitate was filtered and washed with water. The filter cake was dried by vacuum suction overnight to yield the desired product (156.5 mg, 91%) as a milky white powder. LCMS calculated for C ₂₈ H ₂₈ BF ₂ N ₂ O ₅ (M+H)+: m/z = 521.1. Experimental value: 521.1. Step 2 : N-{4-[4- amino- 7-(1-{[ ethyl ( methyl ) amino ] carbonyl } piperidin -4- yl ) pyrrolo [2,1-f][1 ,2,4] triazin -5- yl ]-3- fluorophenyl }-1-(4- fluorophenyl )-2,5- dilateral oxygen -1,2,5,6,7,8 -Hexahydroquinoline -3 - methamide

In a sealed tube, 4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N -ethyl- N -methyl 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4 ,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-2,5-bisoxy-1,2,5,6,7,8- A mixture of hexahydroquinoline-3-formamide (3.8 mg, 0.0074 mmol) and N , N -diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and The mixture was stirred together with water (14 μL), then bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (1.9 mg, 39%). LCMS calculated for C ₃₇ H ₃₇ F ₂ N ₈ O ₄ (M+H)+: m/z = 695.3. Experimental value: 695.3. Example 59. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tri Azin -5- yl } phenyl )-1-(4- fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquinoline -3- carboxylic acid amine

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl ]Ethanol (10 mg, 0.007 mmol) (prepared in Example 52, Step 1), 1-(4-fluorophenyl)-2,5-bisoxy- N- [4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2,5,6,7,8-hexahydroquinoline-3-methamide ( A mixture of 3.7 mg, 0.0074 mmol) (prepared in Example 57, Step 1) and N , N -diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and water (14 μl), and then added bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol). The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (2.1 mg, 47%). LCMS calculated for C ₃₅ H ₃₅ FN ₇ O ₄ (M+H)+: m/z = 636.3. Experimental value: 636.3. Example 60. N -(4-{4- amino- 7-[1-(2- hydroxyethyl ) piperidin -4- yl ] pyrrolo [2,1- f ][1,2,4] tris Azin -5- yl }-3- fluorophenyl )-1-(4- fluorophenyl )-2,5- bisoxy -1,2,5,6,7,8 - hexahydroquinoline- 3- methamide

In a sealed tube, 2-[4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl ] Ethanol (10 mg, 0.007 mmol) (prepared in Example 52, Step 1), 1-(4-fluorophenyl)- N -[3-fluoro-4-(4,4,5,5-tetramethyl (1,3,2-dioxaboropentan-2-yl)phenyl]-2,5-dioxy-1,2,5,6,7,8-hexahydroquinoline-3- A mixture of formamide (3.8 mg, 0.0074 mmol) (prepared in Example 58, Step 1) and N , N -diisopropylethylamine (0.004 mL, 0.02 mmol) in 1,4-dioxane (0.1 mL) and water (14 μL) were stirred together, and then bis(tri-tert-butylphosphine)palladium (1.8 mg, 0.004 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 50 min. The crude material was diluted with MeOH, filtered and analyzed by preparative LC-MS (pH = 2 method; Waters SunFire PrepC18 5 μm OBD ^™ column, 30×100 mm, 60 mL/min, with MeCN and water with 0.1% TFA Gradient elution) was purified to yield the desired product as a white powder (2.4 mg, 52%). LCMS calculated for C ₃₅ H ₃₄ F ₂ N ₇ O ₄ (M+H)+: m/z = 654.3. Experimental value: 654.3. Example 61. N -(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] Triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : Diethyl 2-((3 - phenylureido ) methylene ) malonate

Diethyl (aminomethylene)malonate (6.0 g, 32 mmol) and phenyl isocyanate (3.8 mL, 35 mmol) were dissolved in 1,2-dichloroethane (20 mL) at room temperature. ), N , N -diisopropylethylamine (7.2 mL, 42 mmol) was added to the mixture. The reaction mixture was then stirred at 70°C overnight, cooled to room temperature, _Et2O (50 mL) was added and stirred for a further 30 min. The resulting solid was collected by filtration, washed with diethyl ether and dried to yield the product as a white solid (4.88 g, 50%). LCMS calculated for C ₁₅ H ₁₉ N ₂ O ₅ (M+H) ⁺ : m/z = 307.1. Experimental value: 307.2. Step 2 : Ethyl 2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- carboxylate

Add diethyl 2-((3-phenyluido)methylene)malonate (4.88 g, 15.9 mmol) from the previous step and 2.5 M NaOEt in EtOH (13 mL, 32 mmol) in EtOH ( 20 mL) was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc, washed/acidified with 1 N citric acid, washed with water, brine _, dried over _Na2SO4 and concentrated to afford the crude product as a white solid, which was used directly in the next step (4.1 g , 99%). LCMS calculated for C ₁₃ H ₁₃ N ₂ O ₄ (M+H) ⁺ : m/z = 261.1. Experimental value: 261.1. Step 3 : 1- Isopropyl -2,4- bisoxy -3- phenyl - 1,2,3,4- tetrahydropyrimidine -5- carboxylate ethyl ester

Combine ethyl 2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (1.50 g, 5.76 mmol) from the previous step, 2-iodopropane (1.2 mL, 12 mmol) and Cs ₂ CO ₃ (5.6 g, 17 mmol) in DMF (20 mL) was stirred at 50 °C for 5 h. The reaction mixture was then cooled to room _temperature , diluted with EtOAc, washed with water, brine, dried over _Na2SO4 and concentrated to provide crude product, which was used directly in the next step. LCMS calculated for C ₁₆ H ₁₉ N ₂ O ₄ (M+H) ⁺ : m/z = 303.1. Experimental value: 303.1. Step 4 : 1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

Add ethyl 1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate in 4.0 M HCl from the previous step (1.70 g, 5.62 mmol) in 1,4-dioxane (9.8 mL, 39 mmol) and water (2.1 mL) was stirred at 60 °C for 4 h, cooled to room temperature and water was added. The resulting solid was subsequently collected by filtration (washed with water) to yield the product as a white solid (1.1 g, 71%). LCMS calculated for C ₁₄ H ₁₅ N ₂ O ₄ (M+H) ⁺ : m/z = 275.1. Experimental value: 275.1. Step 5 : 1- isopropyl -2,4- bisoxy -3- phenyl -N-(4-(4,4,5,5 -tetramethyl -1,3,2- dioxaboron) Pentan -2- yl ) phenyl )-1,2,3,4- tetrahydropyrimidine - 5-methamide

To 1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (400 mg, 1 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (320 mg, 1.46 mmol) in DMF (8 mL) Et ₃ N (305 μL, 2.19 mmol) was added to the mixture, followed by HATU (665 mg, 1.75 mmol). The resulting mixture was stirred at room temperature for 2 h and water was added. The resulting solid was collected by filtration, washed with water and dried to yield the product as a pale yellow solid (642 mg, 92%). LCMS calculated for C ₂₆ H ₃₁ BN ₃ O ₅ (M+H) ⁺ : m/z = 476.2. Experimental value: 476.2. Step 6 : 4-[4- Amino -5-(4-{[(1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- yl ) carbonyl ] amino } phenyl ) pyrrolo [2,1-f][1,2,4] triazin -7- yl ] piperidine -1- carboxylic acid tert-butyl ester

Add 1-isopropyl-2,4-bisoxy-3-phenyl- N- [4-(4,4,5,5-tetramethyl-1,3,2-di Oxyboropentan-2-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-methamide (642 mg, 1.35 mmol), 4-(4-amino-5-bromopyrrole) tert-butyl[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylate (535 mg, 1.35 mmol) (from Example 32, Step 3), XPhos Pd A mixture of G2 (110 mg, 0.14 mmol) and Na ₂ CO ₃ (290 mg, 2.7 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL) was purged with nitrogen and incubated at 70 °C. Stir for 2 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc, washed with water, _brine , dried over _Na2SO4 , concentrated and purified via column chromatography (0% to 12% MeOH in DCM) to yield a yellow solid The crude product was used directly in the next step (898 mg, 100%). LCMS calculated for C ₃₆ H ₄₁ N ₈ O ₅ (M+H) ⁺ : m/z = 665.3. Experimental value: 665.3. Step 7 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To 4-[4-amino-5-(4-{[(1-isopropyl-2,4-bisoxy-3-phenyl-1,2, 3,4-Tetrahydropyrimidin-5-yl)carbonyl]amino}phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid To a solution of tributyl ester (898 mg, 1.35 mmol) in _CH2Cl2 (10 mL) was added 4.0 M HCl in 1,4 _- dioxane (3.4 mL, 14 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with _Et2O and the solid collected by filtration to give the product (~2HCl salt) as a yellow solid (702 mg, 81%). LCMS calculated for C ₃₁ H ₃₃ N ₈ O ₃ (M+H) ⁺ : m/z = 565.3. Experimental value: 565.3. Step 8 : N-(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2-f][1,2,4 ] Triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

Add N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazine-5- from the previous step at room temperature base)phenyl]-1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2 HCl salt) ( To a solution of 150 mg, 0.24 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (200 μL, 1.4 mmol), followed by N , N -dimethylaminoformamide chloride (65 μL, 0.70 mmol). ). The reaction mixture was stirred at room temperature for 3 h, diluted with _CH2Cl2 (5.0 mL), _washed with water, _dried over _Na2SO4 and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA) and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₄ H ₃₈ N ₉ O ₄ (M+H) ⁺ : m/z = 636.3. Experimental value: 636.3. ¹ H NMR (600 MHz, DMSO) δ 11.01 (s, 1H), 8.67 (s, 1H), 8.10 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.52 (td, J = 6.9 , 1.6 Hz, 2H), 7.49-7.43 (m, 3H), 7.40-7.33 (m, 2H), 6.75 (s, 1H), 4.78 (hept, J = 6.7 Hz, 1H), 3.66 (d, J = 13.1 Hz, 2H), 3.31 (tt, J = 11.8, 3.5 Hz, 1H), 2.86 (t, J = 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J = 10.7 Hz, 2H) , 1.67 (qd, J = 12.6, 3.8 Hz, 2H), 1.43 (d, J = 6.8 Hz, 6H). Example 62. N -(4-(4- amino- 7-(1-( ethyl ( methyl ) aminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1, 2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methyl amide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl] at room temperature -1-Isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2 HCl salt) (from Example 61, Step 7) To a solution of (150 mg, 0.24 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (200 μL, 1.4 mmol), followed by ethyl(methyl)amine methyl chloride (86 mg, 0.70 mmol). The reaction mixture was stirred at room temperature overnight, diluted with _CH2Cl2 (5.0 mL), _washed with water, _dried over _Na2SO4 and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA) and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product (TFA salt) as a white solid. LCMS calculated for C ₃₅ H ₄₀ N ₉ O ₄ (M+H) ⁺ : m/z = 650.3. Experimental value: 650.3. ¹ H NMR (600 MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.09 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.56-7.50 (m, 2H ), 7.50-7.43 (m, 3H), 7.40-7.34 (m, 2H), 6.74 (s, 1H), 4.78 (p, J = 6.8 Hz, 1H), 3.63 (d, J = 13.0 Hz, 2H) , 3.30 (tt, J = 11.8, 3.5 Hz, 1H), 3.12 (q, J = 7.1 Hz, 2H), 2.85 (t, J = 11.8 Hz, 2H), 2.74 (s, 3H), 1.97 (d, J = 10.8 Hz, 2H), 1.67 (qd, J = 12.6, 3.7 Hz, 2H), 1.43 (d, J = 6.8 Hz, 6H), 1.06 (t, J = 7.1 Hz, 3H). Example 63. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl] at room temperature -1-Isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2HCl salt) (from Example 61, Step 7 ) (150 mg, 0.24 mmol) in CH ₂ Cl ₂ (5.0 mL) was added Et ₃ N (200 μL, 1.4 mmol) followed by isobutyryl chloride (30 μL, 0.28 mmol). The reaction mixture was stirred at room temperature for 15 min, diluted with _CH2Cl2 (5.0 mL), _washed with water, _dried over _Na2SO4 and concentrated. The resulting residue was dissolved in MeCN (5% water, 0.5% TFA) and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₅ H ₃₉ N ₈ O ₄ (M+H) ⁺ : m/z = 635.3. Experimental value: 635.3. ¹ H NMR (600 MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.54-7.50 (m, 2H ), 7.49-7.43 (m, 3H), 7.39-7.34 (m, 2H), 6.72 (s, 1H), 4.78 (p, J = 6.8 Hz, 1H), 4.54 (d, J = 12.4 Hz, 1H) , 4.06 (d, J = 12.6 Hz, 1H), 3.41 (tt, J = 11.8, 3.6 Hz, 1H), 3.20 (t, J = 12.5 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H) , 2.69 (t, J = 12.0 Hz, 1H), 2.03 (dd, J = 31.6, 11.8 Hz, 2H), 1.67-1.59 (m, 1H), 1.55-1.47 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H), 1.05-0.97 (m, 6H). Example 64. N -(4-(4- amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl] at room temperature -1-Isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2HCl salt) (from Example 61, Step 7 ) (150 mg, 0.24 mmol) in CH ₂ Cl ₂ (10 mL) was added N , N -diisopropylethylamine (82 μL, 0.47 mmol). The resulting mixture was stirred at room temperature for 15 min, and formaldehyde in water (24 μL, 37wt%, 0.30 mmol) was added to the mixture. The resulting mixture was stirred for 15 min and NaBH(OAc) ₃ (75 mg, 0.35 mmol) was added to the mixture. The reaction mixture was then stirred at room temperature for 15 min, water (2.25 mL) was added, concentrated, dissolved in MeCN (5% water, 0.5% TFA) and analyzed via pH 2 preparative LC/MS (MeCN/water with TFA ) was purified to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₂ H ₃₅ N ₈ O ₃ (M+H) ⁺ : m/z = 579.3. Experimental value: 579.3. ¹ H NMR (600 MHz, DMSO) δ 10.99 (s, 1H), 8.67 (s, 1H), 7.99 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.55-7.50 (m, 2H ), 7.49-7.42 (m, 3H), 7.38-7.34 (m, 2H), 6.63 (s, 1H), 4.79 (p, J = 6.8 Hz, 1H), 3.54 (d, J = 11.3 Hz, 2H) , 3.41-3.34 (m, 1H), 3.21-3.12 (m, 2H), 2.82 (d, J = 4.6 Hz, 3H), 2.27 (d, J = 13.9 Hz, 2H), 1.93-1.84 (m, 2H ), 1.43 (d, J = 6.8 Hz, 6H). Example 65. N -(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] Triazin -5- yl ) phenyl )-3-(4- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5 -Formamide _

This compound was prepared according to a synthetic sequence similar to Example 61. LCMS calculated for C ₃₄ H ₃₇ FN ₉ O ₄ (M+H) ⁺ : m/z = 654.3. Experimental value: 654.3. ¹ H NMR (600 MHz, DMSO) δ 10.98 (s, 1H), 8.67 (s, 1H), 8.08 (s, 1H), 7.83-7.75 (m, 2H), 7.48-7.45 (m, 2H), 7.45 -7.41 (m, 2H), 7.38-7.32 (m, 2H), 6.73 (s, 1H), 4.81-4.75 (m, 1H), 3.66 (d, J = 13.1 Hz, 2H), 3.34-3.27 (m , 1H), 2.86 (t, J = 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J = 10.7 Hz, 2H), 1.71-1.63 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H). Example 66. N- (4-(4- amino- 7-(1-( ethyl ( methyl ) aminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1, 2,4] triazin -5- yl ) phenyl )-3-(4- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydro Pyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 62. LCMS calculated for C ₃₅ H ₃₉ FN ₉ O ₄ (M+H) ⁺ : m/z = 668.3. Experimental value: 668.2. H NMR (600 MHz, DMSO) δ 10.98 (s, 1H), 8.67 (s, 1H), 8.07 (s, 1H), 7.83-7.76 (m, 2H), 7.50-7.41 (m, 4H), 7.39- 7.33 (m, 2H), 6.73 (s, 1H), 4.82-4.73 (m, 1H), 3.63 (d, J = 13.1 Hz, 2H), 3.34-3.25 (m, 1H), 3.12 (q, J = 7.1 Hz, 2H), 2.85 (t, J = 11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d, J = 10.6 Hz, 2H), 1.73-1.61 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H), 1.06 (t, J = 7.1 Hz, 3H). Example 67. N -(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] Triazin -5- yl ) phenyl )-1- ethyl -3-(4- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Formamide

This compound was prepared according to a synthetic sequence similar to Example 61. LCMS calculated for C ₃₃ H ₃₅ FN ₉ O ₄ (M+H) ⁺ : m/z = 640.3. Experimental value: 640.3. ¹ H NMR (600 MHz, DMSO) δ 10.97 (s, 1H), 8.87 (s, 1H), 8.09 (s, 1H), 7.82-7.76 (m, 2H), 7.48-7.40 (m, 4H), 7.38 -7.33 (m, 2H), 6.74 (s, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.66 (d, J = 13.1 Hz, 2H), 3.34-3.27 (m, 1H), 2.86 ( t, J = 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J = 10.6 Hz, 2H), 1.71-1.62 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). Example 68. N -(4-(4- amino- 7-(1-( morpholine -4- carbonyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] Triazin -5- yl ) phenyl )-1- ethyl -3-(4- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methyl amide

This compound was prepared according to a synthetic sequence similar to Example 61. LCMS calculated for C ₃₅ H ₃₇ FN ₉ O ₅ (M+H) ⁺ : m/z = 682.3. Experimental value: 682.3. ¹ H NMR (600 MHz, DMSO) δ 10.97 (s, 1H), 8.86 (s, 1H), 8.08 (s, 1H), 7.82-7.76 (m, 2H), 7.48-7.39 (m, 4H), 7.39 -7.31 (m, 2H), 6.72 (s, 1H), 4.02 (q, J = 7.1 Hz, 2H), 3.72 (d, J = 13.1 Hz, 2H), 3.59-3.54 (m, 4H), 3.37- 3.28 (m, 1H), 3.16-3.11 (m, 4H), 2.92 (t, J = 11.8 Hz, 2H), 1.98 (d, J = 10.7 Hz, 2H), 1.71-1.61 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). Example 69. N- (4-(4- amino- 7-(1-( ethyl ( methyl ) aminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1, 2,4] triazin -5- yl ) phenyl )-3-(2- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydro Pyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 62. LCMS calculated for C ₃₅ H ₃₉ FN ₉ O ₄ (M+H) ⁺ : m/z = 668.3. Experimental value: 668.3. ¹ H NMR (600 MHz, DMSO) δ 10.83 (s, 1H), 8.72 (s, 1H), 8.07 (s, 1H), 7.82-7.77 (m, 2H), 7.59-7.51 (m, 2H), 7.49 -7.35 (m, 4H), 6.73 (s, 1H), 4.81-4.73 (m, 1H), 3.63 (d, J = 13.1 Hz, 2H), 3.34-3.26 (m, 1H), 3.12 (q, J = 7.1 Hz, 2H), 2.85 (t, J = 11.7 Hz, 2H), 2.74 (s, 3H), 1.98 (d, J = 10.6 Hz, 2H), 1.67 (qd, J = 12.6, 3.7 Hz, 2H ), 1.44 (d, J = 6.8 Hz, 6H), 1.06 (t, J = 7.1 Hz, 3H). Example 70. N -(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] Triazin -5- yl ) phenyl )-3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5 -Formamide _

This compound was prepared according to a synthetic sequence similar to Example 61. LCMS calculated for C ₃₄ H ₃₇ FN ₉ O ₄ (M+H) ⁺ : m/z = 654.3. Experimental value: 654.2. ¹ H NMR (400 MHz, DMSO) δ 10.94 (s, 1H), 8.68 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.63-7.52 (m, 1H ), 7.47 (d, J = 8.6 Hz, 2H), 7.38-7.29 (m, 2H), 7.25 (d, J = 8.2 Hz, 1H), 6.74 (s, 1H), 4.78 (p, J = 6.8 Hz , 1H), 3.66 (d, J = 13.0 Hz, 2H), 3.37-3.20 (m, 1H), 2.87 (q, J = 11.3, 10.6 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J = 10.8 Hz, 2H), 1.75-1.59 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H). Example 71. N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxamide

This compound was prepared according to a synthetic sequence similar to Example 63. LCMS calculated for C ₃₅ H ₃₈ FN ₈ O ₄ (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. ¹ H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.68 (s, 1H), 8.06 (s, 1H), 7.82-7.76 (m, 2H), 7.61-7.53 (m, 1H), 7.47 -7.43 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.22 (m, 1H), 6.72 (s, 1H), 4.78 (p, J = 6.8 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.45-3.37 (m, 1H), 3.20 (q, J = 10.7, 8.7 Hz, 1H), 2.90 (dq, J = 13.5, 6.7 Hz, 1H), 2.69 (t, J = 12.1 Hz, 1H), 2.03 (dd, J = 31.3, 11.9 Hz, 2H), 1.67-1.47 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H), 1.04-0.98 (m, 6H). Example 72. N -(4-(4- amino- 7-(1-( dimethylaminomethyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] Triazin -5- yl ) phenyl )-1- ethyl -3-(3- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Formamide

This compound was prepared according to a synthetic sequence similar to Example 61. LCMS calculated for C ₃₃ H ₃₅ FN ₉ O ₄ (M+H) ⁺ : m/z = 640.3. Experimental value: 640.3. ¹ H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.88 (s, 1H), 8.07 (s, 1H), 7.83-7.75 (m, 2H), 7.57 (ddd, J = 9.0, 7.9, 6.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.36-7.31 (m, 2H), 7.25 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 6.73 (s, 1H), 4.02 (q , J = 7.1 Hz, 2H), 3.66 (d, J = 13.1 Hz, 2H), 3.34-3.26 (m, 1H), 2.86 (t, J = 11.7 Hz, 2H), 2.75 (s, 6H), 1.97 (d, J = 10.7 Hz, 2H), 1.72-1.61 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H). Example 73. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- ethyl -3-(3- fluorophenyl )-2,4- bisoxy -1,2,3,4 -tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 63. LCMS calculated for C ₃₄ H ₃₆ FN ₈ O ₄ (M+H) ⁺ : m/z = 639.3. Experimental value: 639.2. ¹ H NMR (600 MHz, DMSO) δ 10.94 (s, 1H), 8.88 (s, 1H), 8.10 (s, 1H), 7.84-7.73 (m, 2H), 7.60-7.52 (m, 1H), 7.49 -7.43 (m, 2H), 7.38-7.30 (m, 2H), 7.25 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H), 6.75 (s, 1H), 4.54 (d, J = 12.4 Hz, 1H ), 4.11-3.97 (m, 3H), 3.41 (tt, J = 11.8, 3.6 Hz, 1H), 3.20 (t, J = 12.3 Hz, 1H), 2.94-2.85 (m, 1H), 2.69 (t, J = 12.0 Hz, 1H), 2.03 (dd, J = 31.1, 12.1 Hz, 2H), 1.69-1.45 (m, 2H), 1.30 (t, J = 7.1 Hz, 3H), 1.07-0.96 (m, 6H ). Example 74. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) Phenyl )-2,5- dilateral oxy -1- phenyl -1,2,5,6,7,8- hexahydroquinoline -3- methamide

This compound was prepared according to a synthetic sequence similar to Example 57. LCMS calculated for C ₃₇ H ₃₈ N ₇ O ₄ (M+H) ⁺ : m/z = 644.3. Experimental value: 644.3. ¹ H NMR (600 MHz, DMSO) δ 11.56 (s, 1H), 8.95 (s, 1H), 7.99 (s, 1H), 7.87-7.77 (m, 2H), 7.69-7.61 (m, 2H), 7.60 -7.56 (m, 1H), 7.50-7.39 (m, 4H), 6.66 (s, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.44- 3.36 (m, 1H), 3.25-3.14 (m, 1H), 2.95-2.86 (m, 1H), 2.73-2.65 (m, 1H), 2.57-2.48 (m, 4H), 2.11-1.94 (m, 4H ), 1.62 (d, J = 8.8 Hz, 1H), 1.50 (d, J = 8.9 Hz, 1H), 1.01 (dd, J = 9.9, 6.9 Hz, 6H). Example 75. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl )-3- fluorophenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

According to a synthetic sequence similar to Example 63, 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline was used instead of 4-( This compound was prepared from 4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₅ H ₃₈ FN ₈ O ₄ (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. ¹ H NMR (400 MHz, DMSO) δ 11.10 (s, 1H), 8.68 (s, 1H), 8.05 (s, 1H), 7.89 (dd, J = 12.4, 2.0 Hz, 1H), 7.52 (dd, J = 8.1, 6.6 Hz, 2H), 7.49-7.43 (m, 2H), 7.41-7.32 (m, 3H), 6.68 (s, 1H), 4.82-4.75 (m, 1H), 4.54 (d, J = 13.2 Hz, 1H), 4.06 (d, J = 13.0 Hz, 1H), 3.45-3.37 (m, 1H), 3.20 (t, J = 12.2 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.72-2.62 (m, 1H), 2.12-1.93 (m, 2H), 1.69-1.47 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H), 1.01 (width, 6H). Example 76. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-3-(2,5- difluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 63, using 1,4-difluoro-2-isocyanobenzene instead of isocyanoxybenzene. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₅ H ₃₇ F ₂ N ₈ O ₄ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.2. ¹ H NMR (400 MHz, DMSO) δ 10.76 (s, 1H), 8.73 (s, 1H), 8.04 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.59-7.49 (m, 2H ), 7.47 (d, J = 8.6 Hz, 3H), 6.71 (s, 1H), 4.79 (p, J = 6.8 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.08 (d, J = 12.4 Hz, 1H), 3.42 (t, J = 11.8 Hz, 1H), 3.26-3.15 (m, 1H), 2.91 (p, J = 6.7 Hz, 1H), 2.75-2.64 (m, 1H), 2.11 -1.96 (m, 2H), 1.58 (m, J = 10.6 Hz, 2H), 1.45 (dd, J = 6.7, 3.1 Hz, 6H), 1.03 (d, J = 5.5 Hz, 6H). Example 77. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl )-3- methylphenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

According to the synthesis sequence similar to Example 63, 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline was used instead of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline to prepare this compound. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₆ H ₄₁ N ₈ O ₄ (M+H) ⁺ : m/z = 649.3. Experimental value: 649.3. Example 78. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3-( pyridin -3- yl )-1,2,3,4 -tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 63, using 3-isocyanoxypyridine instead of isocyanoxybenzene. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₄ H ₃₈ N ₉ O ₄ (M+H) ⁺ : m/z = 636.3. Experimental value: 636.3. ¹ H NMR (500 MHz, DMSO) δ 10.89 (s, 1H), 8.70 (s, 1H), 8.67 (dd, J = 4.8, 1.4 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.92-7.86 (m, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.61 (dd, J = 7.9, 4.6 Hz, 1H), 7.46 (d, J = 8.6 Hz , 2H), 6.75 (s, 1H), 4.83-4.76 (m, 1H), 4.54 (d, J = 11.9 Hz, 1H), 4.07 (d, J = 12.0 Hz, 1H), 3.46-3.36 (m, 1H), 3.20 (t, J = 12.6 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.69 (t, J = 11.7 Hz, 1H), 2.10-1.95 (m, 2H), 1.69- 1.48 (m, 2H), 1.44 (d, J = 6.8 Hz, 6H), 1.01 (t, J = 6.8 Hz, 6H). Example 79. ( R ) -N- (4-(4- amino- 7-(1-(2- hydroxypropyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1, 2,4] triazin -5- yl ) phenyl )-1- ethyl -3-(4- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -1- Ethyl -3-(4- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Step 1 to Step 7 of Example 61, using 1-fluoro-4-isocyanobenzene instead of isocyanate and iodoethane instead of 2-iodopropane. LCMS calculated for C ₃₀ H ₃₀ FN ₈ O ₃ (M+H) ⁺ : m/z = 569.2. Experimental value: 569.3. Step 2 : (R)-N-(4-(4- amino- 7-(1-(2- hydroxypropyl ) piperidin -4- yl ) pyrrolo [1,2-f][1, 2,4] triazin -5- yl ) phenyl )-1- ethyl -3-(4- fluorophenyl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl]-1-ethyl Methyl-3-(4-fluorophenyl)-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-methamide (~2 HCl) (50.0 mg, 0.088 mmol) To a mixture of ( R )-2-hydroxypropionic acid (16 mg, 0.18 mmol) in DMF (3 mL) was added HATU (70 mg, 0.18 mmol), followed by Et ₃ N (61 μM, 0.44 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with MeCN (with 5% water, 0.5% TFA) and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid ( TFA salt). LCMS calculated for C ₃₃ H ₃₄ FN ₈ O ₅ (M+H) ⁺ : m/z = 641.3. Experimental value: 641.3. ¹ H NMR (500 MHz, DMSO) δ 10.95 (s, 1H), 8.85 (s, 1H), 8.05 (s, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.48-7.38 (m, 4H ), 7.37-7.30 (m, 2H), 6.69 (d, J = 11.8 Hz, 1H), 4.53-4.40 (m, 1H), 4.10 (d, J = 11.4 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.46-3.37 (m, 2H), 3.17 (m, 1H), 2.75 (m, 1H), 2.02 (d, J = 10.9 Hz, 2H), 1.50 (m, 2H), 1.29 ( t, J = 7.1 Hz, 3H), 1.18 (d, J = 6.3 Hz, 3H). Example 80. N -(4-(4- amino- 7-(1-( cyclopropanecarbonyl ) piperidin -4- yl ) pyrrolo [1,2- f ][1,2,4 ] triazine- 5- yl ) phenyl )-1-(2- hydroxypropyl )-2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 1-(2-( tert-butyldimethylsiloxy ) propyl )-2,4- bisoxy -3- phenyl -1,2,3,4 - tetrahydropyrimidine- 5- Ethyl formate

Ethyl 2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (150 mg, 0.58 mmol) (from Example 61, Step 2), (( A mixture of 1-bromoprop-2-yl)oxy)(tert-butyl)dimethylsilane (292 mg, 1.15 mmol) and CsCO ₃ (563 mg, 1.73 mmol) in DMF (5 mL) was dissolved in 100 Stir at ℃ for 5 h. The reaction mixture was then cooled to room _temperature , diluted with EtOAc, washed with water, brine, dried over _Na2SO4 and concentrated to give crude product, which was used directly in the next step. LCMS calculated for C ₂₂ H ₃₃ N ₂ O ₅ Si (M+H) ⁺ : m/z = 433.2. Experimental value: 433.2. Step 2 : 1-(2- hydroxypropyl )-2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

1-(2-((tert-Butyldimethylsilyl)oxy)propyl)-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine -A mixture of ethyl 5-formate (249 mg, 0.58 mmol) in 4 M HCl (1.44 mL, 5.76 mmol) and water (0.50 mL) in 1,4-dioxane was stirred at 70°C for 3 h. Cool to room temperature and concentrate. The resulting material was subsequently purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a yellow oil, which was used directly in the next step. LCMS calculated for C ₁₄ H ₁₅ N ₂ O ₅ (M+H) ⁺ : m/z = 291.1. Experimental value: 291.0. Step 3 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -1-(2- Hydroxypropyl )-2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

According to the synthetic sequence similar to step 5 to step 7 of Example 61, use 1-(2-hydroxypropyl)-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine -5-carboxylic acid was substituted for 1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid to prepare this compound (~2 HCl salt) . LCMS calculated for C ₃₁ H ₃₃ N ₈ O ₄ (M+H) ⁺ : m/z = 581.3. Experimental value: 581.3. Step 4 : N-(4-(4- amino- 7-(1-( cyclopropanecarbonyl ) piperidin -4- yl ) pyrrolo [1,2-f][1,2,4 ] triazine- 5- yl ) phenyl )-1-(2- hydroxypropyl )-2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene at room temperature base)-1-(2-hydroxypropyl)-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2 HCl salt) To a mixture of cyclopropanecarboxylic acid (25 mg, 0.038 mmol), cyclopropanecarboxylic acid (3.4 µl, 0.042 mmol) and HATU (29 mg, 0.077 mmol) in DMF (1.0 mL) was added Et ₃ N (0.027 mL, 0.191 mmol). The reaction mixture was stirred at room temperature for 2 h and the resulting mixture was purified directly via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (pair of enantiomers) (TFA) as a white solid salt). LCMS calculated for C ₃₅ H ₃₇ N ₈ O ₅ (M+H) ⁺ : m/z = 649.3. Experimental value: 649.3. Example 81. N- (4-(4- amino- 7-(1-(2-( dimethylamino )-2- pentoxyethyl ) piperidin -4- yl ) pyrrolo [1,2 - f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetra Hydropyrimidine -5- methamide

N -(4-(4-Amino-7-(piperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl)-1 -Isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxamide (~2 HCl salt) (from Example 61, Step 7) A mixture of (180 mg, 0.28 mmol), 2-bromo- N , N -dimethylacetamide (94 mg, 0.57 mmol) and Et ₃ N (0.197 ml, 1.41 mmol) in DMF (2.5 ml) was added. Stir at room temperature for 3 h. The reaction mixture was diluted with MeOH and purified directly via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₅ H ₄₀ N ₉ O ₄ (M+H) ⁺ : m/z = 650.3. Experimental value: 650.3. ¹ H NMR (600 MHz, DMSO) δ 11.00 (s, 1H), 8.67 (s, 1H), 8.03 (s, 1H), 7.80 (d, J = 8.5 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.49-7.39 (m, 3H), 7.37 (d, J = 7.3 Hz, 2H), 6.66 (s, 1H), 4.82-4.72 (m, 1H), 4.28 (s, 2H), 3.60 (d, J = 11.6 Hz, 2H), 3.47-3.34 (m, 1H), 3.26-3.12 (m, 2H), 2.96 (s, 3H), 2.92 (s, 3H), 2.31-2.22 (m, 2H ), 2.12-2.01 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H). Example 82. N -(4-(4- Amino- 7-(1-(1- methyl -2- pyrrolide -3- yl ) piperidin -4- yl ) pyrrolo [1,2 - f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetra Hydropyrimidine -5- methamide

According to the synthesis sequence similar to Example 81, 3-bromo-1-methylpyrrolidin-2-one was used instead of 2-bromo- N , N -dimethylacetamide and the reaction mixture was heated at 75°C for 1 h. This compound was prepared instead by stirring at room temperature for 3 h. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (a pair of enantiomers) as a white solid (TFA salt). LCMS calculated for C ₃₆ H ₄₀ N ₉ O ₄ (M+H) ⁺ : m/z = 662.3. Experimental value: 662.3. Example 83. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3-( pyridin -2- yl )-1,2,3,4- tetrahydropyrimidine -5- carboxamide Step 1 : 1-(4-(4- amino -5- bromopyrrolo [1,2-f][1,2,4] triazin -7- yl ) piperidin -1- yl )-2- Methylpropan -1- one

To 5-bromo-7-(piperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (~2 HCl) (939 mg, 2.54 mmol) (from Example 32, step 4) To the mixture in _CH2Cl2 (25 ml ₎ was added _Et3N (1.77 ml, 12.7 mmol). The reaction mixture was stirred at room temperature for 1 h and isobutyryl chloride (0.29 ml, 2.80 mmol) was added. The reaction mixture was then stirred at room temperature for 30 min, concentrated and the resulting material purified via column chromatography (0% to 10% MeOH _{in CH2Cl2} ) to yield the product as a yellow solid (602 mg, 65% ). LCMS calculated for C ₁₅ H ₂₁ BrN ₅ O (M+H) ⁺ : m/z = 366.1. Experimental value: 366.1. Step 2 : 1-(4-(4- amino- 5-(4- aminophenyl ) pyrrolo [1,2-f][1,2,4] triazin - 7- yl ) piperidine- 1- yl )-2- methylpropan -1- one

First, 1-(4-(4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methyl Propan-1-one (400 mg, 1.09 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (251 mg, A mixture of XPhos Pd G2 (86 mg, 0.11 mmol) and Na ₂ CO ₃ (232 mg, 2.18 mmol) in 1,4-dioxane (7.5 ml)/water (1.5 ml) was added with N ₂ Purge and stir at 85 °C for 3 h. The reaction mixture was then cooled to room temperature, filtered through a pad of celite (washed with _EtOAc ), concentrated and purified via column chromatography (0% to 10% MeOH in _CH2Cl2 ) to yield the product as a yellow solid (398 mg, 96%). LCMS calculated value for C ₂₁ H ₂₇ N ₆ O (M+H) ⁺ : m/z = 379.2. Experimental value: 379.2. Step 3 : Diethyl 2-((3- pyridin -2- ylureido ) methylene ) malonate

Diethyl 2-(aminomethylene)malonate (3.0 g, 16.0 mmol) and 2-isocyanooxypyridine (2.02 g, 16.8 mmol) were dissolved in 1,2-dichloroethyl at room temperature. To the mixture in alkanes (9.0 mL) was added N , N -diisopropylethylamine (3.6 mL, 20.8 mmol). The reaction mixture was then stirred at 70°C overnight, cooled to room temperature and purified directly via column chromatography (0% to 15% MeOH _{in CH2Cl2} ) to yield the product (3.18 g, 65%). LCMS calculated for C ₁₄ H ₁₈ N ₃ O ₅ (M+H) ⁺ : m/z = 308.1. Experimental value: 308.1. Step 4 : 1- isopropyl -2,4- bisoxy -3-( pyridin -2- yl )-1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

Diethyl 2-((3-(pyridin-2-yl)ureido)methylene)malonate (3.18 g, 10.4 mmol) and 2.5 M NaOEt in EtOH (6.2 mL, 15.5 mmol) were added in EtOH. (25 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted with EtOAc and washed/acidified with 1 N citric acid solution (30 mL). The organic layer was separated and the aqueous layer was further extracted with 3:1 CHCl ₃ /isopropyl alcohol (30 mL×3). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to provide the crude product 2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5- Ethyl formate, which was used directly in the next step. LCMS calculated for C ₁₂ H ₁₂ N ₃ O ₄ (M+H) ⁺ : m/z = 262.1. Experimental value: 262.2.

Combine crude ethyl 2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate and 2-iodopropane (2.06 mL) from the previous step. , 20.7 mmol) and Cs ₂ CO ₃ (10.1 g, 31.0 mmol) in DMF (35 mL) was stirred at 70 °C for 3 h. The reaction mixture was then cooled to room temperature, diluted with 3:1 CHCl ₃ /isopropanol (75 mL), washed with water, brine, dried over Na ₂ SO ₄ and concentrated to give crude 1-isopropyl-2 , ethyl 4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate, which was used directly in the next step. LCMS calculated for C ₁₅ H ₁₈ N ₃ O ₄ (M+H) ⁺ : m/z = 304.1. Experimental value: 304.1.

Crude ethyl 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate from the previous step was dissolved in 1 , a mixture of 4 M HCl in 4-dioxane (20 mL, 82 mmol) and water (5.0 mL) was stirred at 80°C for 5 h, cooled to room temperature and concentrated. The resulting material was subsequently purified via column chromatography (0% to 15% MeOH _{in CH2Cl2} ) to yield the product as a pale yellow solid (1.50 g, 47% in three steps). LCMS calculated for C ₁₃ H ₁₄ N ₃ O ₄ (M+H) ⁺ : m/z = 276.1. Experimental value: 276.1. Step 5 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3-( pyridin -2- yl )-1,2,3,4- tetrahydropyrimidine -5- carboxamide

To 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (85 mg, 0.31 mmol), 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine- To a mixture of 1-yl)-2-methylpropan-1-one (129 mg, 0.34 mmol) and HATU (141 mg, 0.37 mmol) in DMF (3.5 mL) was added Et ₃ N (0.13 mL, 0.93 mmol) ). _The reaction mixture was stirred at room temperature for 1 h, diluted with _CH2Cl2 and washed with water. The organic layer was separated, dried over _Na2SO4 , concentrated and purified via column chromatography (0% to 10% MeOH _{in CH2Cl2} ) to give the product, which _was subjected to pH 2 preparative LC/MS (MeCN /water with TFA) was further purified to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₄ H ₃₈ N ₉ O ₄ (M+H) ⁺ : m/z = 636.3. Experimental value: 636.3. ¹ H NMR (600 MHz, DMSO) δ 10.86 (s, 1H), 8.71 (s, 1H), 8.63 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.10 (s, 1H), 8.06 (td , J = 7.7, 1.9 Hz, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.61-7.53 (m, 2H), 7.46 (d, J = 8.6 Hz, 2H), 6.76 (s, 1H) , 4.77 (p, J = 6.8 Hz, 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.07 (d, J = 13.0 Hz, 1H), 3.41 (tt, J = 11.8, 3.5 Hz, 1H) , 3.20 (t, J = 12.4 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.69 (t, J = 12.1 Hz, 1H), 2.02 (dd, J = 30.5, 12.4 Hz, 2H) , 1.70-1.48 (m, 2H), 1.44 (d, J = 6.8 Hz, 6H), 1.08-0.93 (m, 6H). Example 84. N -(4-(4- amino- 7-(1,3,5- trimethyl -1 H -pyrazol -4- yl ) pyrrolo [1,2- f ][1,2 ,4] triazin -5- yl ) phenyl )-3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 7-(3,5- dimethyl -1H- pyrazol -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 4- amine

7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (0.32 g, 1.50 mmol), 3,5-dimethyl-4-(4,4,5 ,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H -pyrazole (0.425 g, 1.80 mmol), Na ₂ CO ₃ (0.318 g, 3.0 mmol) and XPhos A mixture of Pd G2 (0.118 g, 0.150 mmol) in 1,4-dioxane (6.0 ml)/water (1.0 ml) was evacuated and refilled twice with _N2 , and the reaction was stirred at 95 °C overnight . The reaction mixture was then cooled to room temperature, diluted with EtOAc, washed with water, _brine , dried over _Na2SO4 , concentrated and purified via column chromatography (0% to 10% MeOH _{in CH2Cl2} ) to yield The crude product is a yellow solid. LCMS calculated value for C ₁₁ H ₁₃ N ₆ (M+H) ⁺ : m/z = 229.1. Experimental value: 229.1. Step 2 : 5- bromo -7-(3,5- dimethyl-1H - pyrazol - 4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 4 - amine

To 7-(3,5-dimethyl-1 H -pyrazol-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (0.23 g, 1.0 mmol) in DMSO (1.0 ml)/MeCN (1.0 ml)/water (20 µL) was added NBS (0.18 g, 1.0 mmol) and the mixture was warmed to room temperature and stirred for 1 h. Water was added to the reaction mixture and the resulting solid was collected by filtration, washed with water and dried to provide the product. LCMS calculated for C ₁₁ H ₁₂ BrN ₆ (M+H) ⁺ : m/z = 307.0. Experimental value: 307.0. Step 3 : N-(4-(4- amino- 7-(3,5- dimethyl -1H- pyrazol -4- yl ) pyrrolo [1,2-f][1,2,4] Triazin -5- yl ) phenyl )-3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Formamide

5-Bromo-7-(3,5-dimethyl-1 H -pyrazol-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (0.123 g, 0.40mmol), 3-(3-fluorophenyl)-1-isopropyl-2,4-bisoxy- N- (4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboropentan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (0.217 g, 0.440 mmol) (according to the same procedure as in Example 61, Step 1 Similar synthesis sequence to step 5, using 1-fluoro-3-isocyanaxobenzene instead of isocyanate), Na ₂ CO ₃ (0.085 g, 0.80 mmol) and XPhos Pd G2 (0.031 g, 0.040 mmol) in 1,4-dioxane (2.0 ml)/water (0.4 ml) was evacuated and refilled twice with _N2 , and the reaction mixture was stirred at 75°C overnight. The resulting mixture was cooled to room temperature, diluted with MeCN (with 5% water, 0.5% TFA), filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product (TFA) as a white solid salt). LCMS calculated for C ₃₁ H ₂₉ FN ₉ O ₃ (M+H) ⁺ : m/z = 594.2. Experimental value: 594.2. Step 4 : N-(4-(4- amino- 7-(1,3,5- trimethyl -1H- pyrazol -4- yl ) pyrrolo [1,2-f][1,2, 4] Triazin -5- yl ) phenyl )-3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4 - tetrahydropyrimidine- 5- methamide

To N -(4-(4-amino-7-(3,5-dimethyl-1 H -pyrazol-4-yl)pyrrolo[2,1- f ][1,2 ,4]triazin-5-yl)phenyl)-3-(3-fluorophenyl)-1-isopropyl-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine -To a mixture of 5-formamide (30.0 mg, 0.051 mmol) and Cs ₂ CO ₃ (32.9 mg, 0.10 mmol) in DMF (1.0 ml) was added iodomethane (3.2 µl, 0.051 mmol) and the reaction mixture was added Stir at room temperature for 1 h. The reaction mixture was then diluted with MeCN (with 5% water, 0.5% TFA), filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₂ H ₃₁ FN ₉ O ₃ (M+H) ⁺ : m/z = 608.3. Experimental value: 608.3. Example 85. N -(4-(4- amino- 7-(6-( dimethylaminemethyl )-4- methylpyridin -3- yl ) pyrrolo [1,2- f ][1 ,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- Formamide Step 1 : 5-(4- amino -5- bromopyrrolo [1,2-f][1,2,4] triazin -7- yl )-N,N,4- trimethylpicolinyl amine

According to the synthesis sequence similar to step 1 to step 2 of Example 84, use N , N , 4-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropenta Alk-2-yl)pyridinamide instead of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl) -1H -pyrazole to prepare this compound. LCMS calculated for C ₁₅ H ₁₆ BrN ₆ O (M+H) ⁺ : m/z = 375.1. Experimental value: 375.0. Step 2 : N-(4-(4- amino- 7-(6-( dimethylaminemethyl )-4- methylpyridin -3- yl ) pyrrolo [1,2-f][1 ,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- Formamide

1-Isopropyl-2,4-dioxy-3-phenyl- N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane -2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-carboxamide (30 mg, 0.063 mmol) (from Example 61, step 5), 5-(4-amino- 5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl) -N , N ,4-trimethylpyridinamide (26 mg, 0.069 mmol), bicyclo Hexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium(1:1)(XPhos Pd G2 ) (5.0 mg, 6.3 µmol) and Na ₂ CO ₃ (13.4 mg, 0.13 mmol) in 1,4-dioxane (1.5 mL)/water (0.3 mL) purged with N ₂ and incubated at 70 °C Stir for 2 h. The reaction mixture was cooled to room temperature, diluted with MeOH, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid. LCMS calculated for C ₃₅ H ₃₄ N ₉ O ₄ (M+H) ⁺ : m/z = 644.3. Experimental value: 644.3. Example 86. 4- Amino -5-(4-(3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide ) phenyl )-N,N- dimethylpyrrolo [2,1-f][1,2,4] triazine -7- methamide Step 1 : 4- Aminopyrrolo [1,2-f][1,2,4] triazine -7- carbonitrile

Add N , N , N' , N' -tetramethylethylenediamine (40 μL, 0.3 mmol), ZnCN (118 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (37 mg , 0.04 mmol) and (9,9-dimethyl-9 H -dibenzopiran-4,5-diyl)bis(diphenylphosphine) (46 mg, 0.080 mmol) were added continuously to the microwave vial A solution of 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (210 mg, 1.0 mmol) in DMF (2.0 mL). The vial was sealed, degassed three times and stirred at 160°C for 8 min under microwave conditions. The reaction mixture was cooled _to room temperature, filtered (washed with _CH2Cl2 ) and concentrated. The resulting material was washed with MeCN and dried to provide crude product, which was used directly in the next step. LCMS calculated for C ₇ H ₆ N ₅ (M+H) ⁺ : m/z = 160.1. Experimental value: 160.0. Step 2 : 4- amino -5- bromopyrrolo [1,2-f][1,2,4] triazine -7- carbonitrile

4-Aminopyrrolo[2,1- f ][1,2,4]triazine-7-carbonitrile (0.10 g, 0.63 mmol) was dissolved in DMSO (1.0 mL)/MeCN (0.6 mL at 0 °C )/water (0.08 mL) was added NBS (0.117 g, 0.66 mmol) and the reaction mixture was stirred at this temperature for 2 h. Water was added and the resulting solid was collected by filtration, washed with water and dried to provide the product. LCMS calculated for C ₇ H ₅ BrN ₅ (M+H) ⁺ : m/z = 238.0. Experimental value: 238.0. Step 3 : 4- Amino -5- bromopyrrolo [1,2-f][1,2,4] triazine -7- carboxylic acid

To 4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazine-7-carbonitrile (50 mg, 0.2 mmol) in 1,4-dioxane (0.4 mL ) was added 12 M HCl in water (0.4 mL). The reaction was stirred at 95 °C for 4 h, cooled to room temperature and concentrated to yield crude product, which was used directly in the next step. LCMS calculated for C ₇ H ₆ BrN ₄ O ₂ (M+H) ⁺ : m/z = 257.0. Experimental value: 257.0. Step 4 : 4- Amino -5- bromo -N,N- dimethylpyrrolo [1,2-f][1,2,4] triazine -7- carboxamide

To 4-amino-5-bromopyrrolo[2,1- f ][1,2,4]triazine-7-carboxylic acid (25 mg, 0.097 mmol) and BOP (60 mg, 0.14 mmol) in DMF ( To the mixture in 1.0 mL) was added 2 M dimethylamine in THF (0.38 mL, 0.75 mmol), followed by Et ₃ N (50 μL, 0.36 mmol). The reaction mixture was stirred at room temperature for 3 h, diluted with EtOAc, washed with saturated _NaHCO3 solution, water, _brine , dried over _Na2SO4 and concentrated to give the product, which was used directly in the next step. LCMS calculated for C ₉ H ₁₁ BrN ₅ O (M+H) ⁺ : m/z = 284.0. Experimental value: 284.0. Step 5 : 4- amino -5-(4-(3-(3- fluorophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide ) phenyl )-N,N- dimethylpyrrolo [2,1-f][1,2,4] triazine -7- methamide

3-(3-Fluorophenyl)-1-isopropyl-2,4-bisoxy- N- [4-(4,4,5,5-tetramethyl-1,3,2- Dioxaboropentan-2-yl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-methamide (0.020 g, 0.040 mmol) (analogous to steps 1 to 5 of Example 61 Synthesis sequence, use 1-fluoro-3-isocyanobenzene instead of isocyanoxybenzene to prepare), 4-amino-5-bromo- N , N -dimethylpyrrolo[2,1- f ] [1,2,4]Triazine-7-methamide (0.016 g, 0.057 mmol), Na ₂ CO ₃ (9.0 mg, 0.085 mmol) and XPhos Pd G2 (3.3 mg, 0.0042 mmol) in 1,4- The mixture in dioxane (1.0 mL)/water (0.1 mL) was evacuated and refilled with _N2 and stirred at 75 °C for 5 h. The resulting mixture was then cooled to room temperature, diluted with MeCN (with 5% water, 0.5% TFA), filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to give the product as a white solid ( TFA salt). LCMS calculated for C ₂₉ H ₂₈ FN ₈ O ₄ (M+H) ⁺ : m/z = 571.2. Experimental value: 571.1. Example 87. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -3-(1- methyl - 1H - pyrazol -4- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1. Diethyl 2-((3-(1- methyl -1H- pyrazol -4- yl ) ureido ) methylene ) malonate

A mixture of 1-methyl-1 H -pyrazol-4-amine (0.097 g, 1.0 mmol) and 1,1'-carbonyldiimidazole (0.178 g, 1.100 mmol) in DMSO (1 mL) was stirred at room temperature. After stirring for 1 h, diethyl 2-(aminomethylene)malonate (0.187 g, 1.00 mmol) was added to this solution. The reaction mixture was stirred at 80°C overnight, cooled to room temperature and purified directly via column chromatography (0% to 100% EtOAc in hexane) to yield the product (0.204 g, 66%). LCMS calculated for C ₁₃ H ₁₉ N ₄ O ₅ (M+H) ⁺ : m/z = 311.1. Experimental value: 311.2. Step 2. Ethyl 3-(1- methyl -1H- pyrazol -4- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxylate

2.5 M NaOEt (0.39 mL, 0.99 mmol) in EtOH and diethyl 2-((3-(1-methyl-1 H -pyrazol-4-yl)ureido)methylene)malonate A mixture of (0.204 g, 0.66 mmol) in EtOH (2 mL) was stirred at room temperature for 3 h. The resulting mixture was diluted _{with CH2Cl2} and acidified with 1 N HCl to pH approximately 7. The organic layer was separated and the aqueous layer was _further extracted with 10% MeOH in _CH2Cl2 . The combined organic layers were dried _{over Na2SO4} and concentrated to provide crude product (0.172 g, 99%), which was used directly in the next step. LCMS calculated for C ₁₁ H ₁₃ N ₄ O ₄ (M+H) ⁺ : m/z = 265.1. Experimental value: 265.2. Step 3. 1- isopropyl -3-(1- methyl -1H- pyrazol -4- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Ethyl formate

Ethyl 3-(1-methyl-1 H -pyrazol-4-yl)-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylate (0.172 g, A mixture of 0.65 mmol), 2-iodopropane (0.13 mL, 1.30 mmol) and Cs ₂ CO ₃ (0.636 g, 1.95 mmol) in DMF (2 mL) was stirred at 80 °C for 3 h. The reaction mixture was then cooled _to room temperature and filtered (washed with _CH2Cl2 ). The filtrate was diluted with 10% MeOH _{in CH2Cl2} , washed with water, brine, dried over _Na2SO4 and concentrated to give _crude product (0.195 g, 98%) which was used directly in the next step. LCMS calculated for C ₁₄ H ₁₉ N ₄ O ₄ (M+H) ⁺ : m/z = 307.1. Experimental value: 307.1. Step 4. 1- isopropyl -3-(1- methyl -1H- pyrazol -4- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Formic acid

1-Isopropyl-3-(1-methyl-1 H -pyrazol-4-yl)-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid A mixture of ethyl ester (0.195 g, 0.64 mmol) in 4 M HCl in dioxane (1.27 mL) and water (0.32 mL) was stirred at 80 °C overnight. The reaction mixture was then cooled to room temperature, diluted with water (3 mL) and neutralized to pH ~5 with IN NaOH solution. The resulting mixture was extracted with 10% MeOH _{in CH2Cl2} (3 mL×3) and the combined organic layers were dried over _Na2SO4 and concentrated to give _crude product (0.172 g, 97%), which was used directly In the next step. LCMS calculated for C ₁₂ H ₁₅ N ₄ O ₄ (M+H) ⁺ : m/z = 279.1. Experimental value: 279.1. Step 5. N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -3-(1- methyl -1H- pyrazol -4- yl )-2,4- bisoxy -1,2,3,4 - tetrahydropyrimidine- 5- methamide

To 1-isopropyl-3-(1-methyl-1 H -pyrazol-4-yl)-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid To a mixture of 1-(4-(4-amino-5-(4-aminophenyl))pyrrolo (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added [2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (0.019 g, 0.050 mmol) (from Example 83, Step 2) and _Et3N (0.021 ml, 0.15 mmol). The mixture was stirred at room temperature for 2 h, diluted with MeOH, adjusted to pH ~2 with TFA and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₃ H ₃₉ N ₁₀ O ₄ (M+H) ⁺ : m/z = 639.3. Experimental value: 639.3. Example 88. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -3-(1- methyl - 1H - pyrazol -3- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 87, using 1-methyl-1 H -pyrazol-3-amine instead of 1-methyl-1 H -pyrazol-4-amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₃ H ₃₉ N ₁₀ O ₄ (M+H) ⁺ : m/z = 639.3. Experimental value: 639.3. Example 89. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -3-(2- methylthiazol -5- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid amine

This compound was prepared according to a synthetic sequence similar to Example 87, using 2-methylthiazol-5-amine instead of 1-methyl- 1H -pyrazol-4-amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value for C ₃₃ H ₃₈ N ₉ O ₄ S (M+H) ⁺ : m/z = 656.3. Experimental value: 656.3. Example 90. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-3- cyclohexyl -1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 3- cyclohexyl -1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

This compound was prepared according to a synthetic sequence similar to Step 1 to Step 4 of Example 61, using isocyanoxycyclohexane instead of isocyanoxybenzene. LCMS calculated for C ₁₄ H ₂₁ N ₂ O ₄ (M+H) ⁺ : m/z = 281.2. Experimental value: 281.1. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-3- cyclohexyl -1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

To 3-cyclohexyl-1-isopropyl-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4] Triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (0.019 g, 0.050 mmol) (from Example 83, step 2) and Et ₃ N (0.021 ml, 0.15 mmol) . The mixture was stirred at room temperature for 2 h, diluted with MeOH, adjusted to pH ~2 with TFA and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₅ H ₄₅ N ₈ O ₄ (M+H) ⁺ : m/z = 641.4. Experimental value: 641.3. Example 91. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-3-(3- cyanophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 3-(3- bromophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

This compound was prepared according to a synthetic sequence similar to step 1 to step 4 of Example 61, using 1-bromo-3-isocyanobenzene instead of isocyanoxybenzene. LCMS calculated for C ₁₄ H ₁₄ BrN ₂ O ₄ (M+H) ⁺ : m/z = 353.0. Experimental value: 353.1. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-3-(3- bromophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxamide

To 3-(3-bromophenyl)-1-isopropyl-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.018 g, 0.050 mmol) and HATU To a mixture of (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1 ,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (0.019 g, 0.050 mmol) (from Example 83, step 2) and Et ₃ N (0.021 ml, 0.150 mmol). The mixture was stirred at room temperature for 2 h and water (4 mL) was added. The resulting solid was collected by filtration, washed with water and dried to yield the product. LCMS calculated for C ₃₅ H ₃₈ BrN ₈ O ₄ (M+H) ⁺ : m/z = 713.2. Experimental value: 713.2. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-3-(3- cyanophenyl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

Place N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine- 5-yl)phenyl)-3-(3-bromophenyl)-1-isopropyl-2,4-bisoxy-1,2,3,4-tetrahydropyrimidine-5-methamide Degassing a mixture of (0.036 g, 0.050 mmol), potassium hexacyanoferrate(II) trihydrate (10.5 mg, 0.025 mmol), tBuXPhos Pd G3 (0.32 mg, 0.40 µmol) and KOAc (0.61 mg, 6.3 µmol) And add N ₂ as supplementary note. Then 1,4-dioxane (0.50 mL) and water (0.50 mL) were added. The mixture was degassed again and _N2 was added, cycled three times. The reaction mixture was then heated at 100 °C for 1 h, cooled to room temperature, diluted with MeOH, adjusted to pH ~2 with TFA and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield TFA Products in salt form. LCMS calculated for C ₃₆ H ₃₈ N ₉ O ₄ (M+H) ⁺ : m/z = 660.3. Experimental value: 660.3. Example 92. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -3-(5- methylisoxazol -3- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- Formamide

This compound was prepared according to a synthetic sequence similar to Example 87, using 5-methylisoxazol-3-amine instead of 1-methyl- 1H -pyrazole-4-amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₃ H ₃₈ N ₉ O ₅ (M+H) ⁺ : m/z = 640.3. Experimental value: 640.3. Example 93. N -(4-(4- amino- 7-(4-( dimethylamino ) cyclohexyl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : (4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohex -3- en - 1- yl ) carbamic acid tertiary Butyl ester

In a sealed vial, combine 7-bromopyrrolo[2,1- f ][1,2,4]triazin-4-amine (300 mg, 1.41 mmol), 4-(4,4,5,5 -Tetramethyl-1,3,2-dioxaboropentan-2-yl)cyclohex-3-enylcarbamate (550 mg, 1.69 mmol), chloro(2-dicyclohexyl) Phosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (55.4 mg, 0.070 mmol) and tripotassium phosphate (0.35 ml, 4.22 mmol) in 1,4-dioxane (10 ml)/water (2.0 ml) was degassed and stirred at 90 °C under N for _2.5 h. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with brine. The organic layer was separated, dried over _Na2SO4 , concentrated and purified by column chromatography (0% _to 10% MeOH _{in CH2Cl2} ) to give the product (400 mg, 86%). LCMS calculated value (M+H) ⁺ for C ₁₇ H ₂₄ N ₅ O ₂ : m/z = 330.2; experimental value: 330.1. Step 2 : (4-(4- Aminopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohexyl ) carbamic acid tert-butyl ester

To (4-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohex-3-en-1-yl)carbamic acid tert-butyl ester (460 mg, 1.40 mmol) in MeOH (25 ml) was added 10% Pd/C (297 mg). The resulting mixture was stirred at 1 atm _H2 (balloon). After 22 h, more 10% Pd/C (160 mg) was added along with CH ₂ Cl ₂ (5 mL). The reaction mixture was then stirred for _an additional 23 h, filtered through celite (washed with _CH2Cl2 ) and concentrated to give crude product (463 mg), which was used directly in the next step. LCMS calculated value (M+H) ⁺ for C ₁₇ H ₂₆ N ₅ O ₂ : m/z = 332.2; experimental value: 332.2. Step 3 : (4-(4- Amino -5- bromopyrrolo [2,1-f][1,2,4] triazin -7- yl ) cyclohexyl ) carbamic acid tert-butyl ester

To (4-(4-Aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexyl)carbamic acid tert-butyl ester (463 mg, 1.40 mmol) in To a solution in DMF (15 ml) was added NBS (249 mg, 1.40 mmol). The resulting mixture was stirred at room temperature overnight. Water was then added to the reaction mixture and the resulting solid was collected by filtration, washed with water and dried to give the product as a yellow solid (443 mg), which was used directly in the next step. LCMS calculated value (M+H) ⁺ for C ₁₇ H ₂₅ BrN ₅ O ₂ : m/z = 410.1; experimental value: 410.1. Step 4 : N-(4-(4- amino- 7-(4- aminocyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ) -1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

(4-(4-Amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)cyclohexyl)carbamic acid tert-butyl ester (27.0 mg, 0.066 mmol), 1-isopropyl-2,4-dioxy-3-phenyl- N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxy Boronpentan-2-yl)phenyl)-1,2,3,4-tetrahydropyrimidine-5-methamide (40.7 mg, 0.086 mmol) (from Example 61, step 5), chloro(2-di Cyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) A mixture of tripotassium phosphate (2.6 mg, 3.3 µmol) and tripotassium phosphate (41.9 mg, 0.197 mmol) in 1,4-dioxane (0.50 mL)/water (0.10 mL) was stirred at 90 °C under N for ₂ h. , cooled to room temperature and partitioned between CH ₂ Cl ₂ and water. The organic layer was separated and concentrated. To the crude residue was added CH ₂ Cl ₂ (400 uL) and TFA (200 µL). The resulting solution was stirred at room temperature for 1 h and concentrated. The crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₂ H ₃₅ N ₈ O ₃ : m/z = 579.3; experimental value: 579.2. Step 5 : N-(4-(4- amino- 7-(4-( dimethylamino ) cyclohexyl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -(4-(4-amino-7-(4-aminocyclohexyl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl)-1 -Isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-methamide (15 mg, 0.022 mmol), formaldehyde in water (37 wt %, 1.6 µL, 0.022 mmol) and Et ₃ N (12 µL, 0.087 mmol) in THF (0.30 ml) was added sodium triacetyloxyborohydride (50 mg, 2.05 mmol). The resulting mixture was stirred at room temperature overnight, filtered and concentrated. The crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₄ H ₃₉ N ₈ O ₃ : m/z = 607.3; experimental value: 607.3. Example 94. N-(4-(4- amino- 7-(1-( cyclopropanecarbonyl ) azetidin -3- yl ) pyrrolo [2,1-f][1,2,4] Triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 7- iodopyrrolo [1,2-f][1,2,4] triazin -4- amine

To a solution of pyrrolo[1,2- f ][1,2,4]triazin-4-amine (1.5 g, 11 mmol) in DMF (10 mL) at room temperature was added N -iodobutane Imide (2.5 g, 11 mmol) was added and the reaction was stirred for 2 h. The reaction mixture was then diluted with EtOAc, washed with water and concentrated. The resulting solid was washed with water and dried to yield the product. LCMS calculated value for C ₆ H ₆ IN ₄ (M+H) ⁺ : m/z = 261.0. Experimental value: 261.2. Step 2 : 3-(4- Aminopyrrolo [1,2-f][1,2,4] triazin -7- yl ) azetidine -1- carboxylic acid tert-butyl ester

Zinc (0.690 g, 10.5 mmol) was suspended in 1,2-dibromoethane (60 μL, 0.70 mmol) in DMF (20 mL). The resulting mixture was stirred at 70 °C for 10 min and cooled to room temperature. Chlorotrimethylsilane (89 μL, 0.70 mmol) was added and stirring continued for 1 h. A solution of 3-iodoazetidine-1-carboxylic acid tert-butyl ester (2.5 g, 8.8 mmol) in DMF (10 mL) was then added and the mixture was stirred at 40 °C for 1 h before adding 7-iodo Pyrro[2,1- f ][1,2,4]triazin-4-amine (2.4 g, 9.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.80 g, 0.88 mmol) and tris-(2-furyl)phosphine (0.41 g, 1.8 mmol) in DMF (12 mL). The reaction mixture was then stirred at 75°C overnight, cooled to room temperature and partitioned between EtOAc and saturated _NH4Cl solution. The organic layer was separated, washed with water, dried over _MgSO4 , concentrated and purified via column chromatography (0% to 100% EtOAc in hexanes) to give the product (1.0 g, 39%). LCMS calculated for C ₁₄ H ₂₀ N ₅ O ₂ (M+H) ⁺ : m/z = 290.2. Experimental value: 290.2. Step 3 : 3-(4- Amino -5- bromopyrrolo [1,2-f][1,2,4] triazin -7- yl ) azetidine -1- carboxylic acid tert-butyl ester

To 3-(4-aminopyrrolo[2,1- f ][1,2,4]triazin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (0.94 To a solution of g, 3.2 mmol) in DMSO/MeCN/water (7.0 mL/3.0 mL/0.2 mL) was added NBS (0.55 g, 3.1 mmol) and the reaction mixture was stirred at this temperature for 2 h. The resulting mixture was diluted with EtOAc, washed with water, concentrated and purified via column chromatography (0% to 100% EtOAc in hexane) to yield the desired product (0.35 g, 29%). LCMS calculated for C ₁₄ H ₁₉ BrN ₅ O ₂ (M+H) ⁺ : m/z = 368.1. Experimental value: 368.0. Step 4 : 3-(4- Amino- 5-(4- aminophenyl ) pyrrolo [1,2-f][1,2,4] triazin - 7- yl ) azetidine- 1- tert-butylformate

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (0.21 g, 0.95 mmol), 3-(4-amino-5 -Bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)azetidine-1-carboxylic acid tert-butyl ester (0.35 g, 0.95 mmol), Cs ₂ CO ₃ (0.62 g, 1.9 mmol) and dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro) A mixture of palladium (1:1) (0.075 g, 0.095 mmol) in 1,4-dioxane/water was stirred at 85 °C for 2 h. The reaction mixture was then cooled to room temperature and purified via column chromatography (0% to 100% EtOAc in hexane) to yield the product (0.28 g, 77%). LCMS calculated for C ₂₀ H ₂₅ N ₆ O ₂ (M+H) ⁺ : m/z = 381.2. Experimental value: 381.3. Step 5 : 3-(4- amino -5-(4-(1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5) -Formamide ) phenyl ) pyrrolo [2,1-f][1,2,4] triazin -7- yl ) azetidine -1- carboxylic acid tert- butyl ester

To 3-[4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]azetidine-1- tert-butyl formate (140 mg, 0.37 mmol) and 1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (110 mg, 0.40 mmol) (from Example 61, step 4) To a mixture in DMF (3.0 mL) was added _Et3N (0.10 mL, 0.74 mmol) followed by HATU (0.17 g, 0.44 mmol). The reaction mixture was stirred at room temperature for 1 h, quenched with water and the resulting solid was collected by filtration and dried to yield the product. LCMS calculated for C ₃₄ H ₃₇ N ₈ O ₅ (M+H) ⁺ : m/z = 637.3. Experimental value: 637.2. Step 6 : N-(4-(4- amino- 7-( azetidin -3- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) Phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

3-(4-Amino-5-(4-(1-isopropyl-2,4-bisoxy-3-phenyl) in CH ₂ Cl ₂ (1 mL) at room temperature -1,2,3,4-tetrahydropyrimidin-5-methamide)phenyl)pyrrolo[1,2- f ][1,2,4]triazin-7-yl)azetidine Alkane-1-carboxylic acid tert-butyl ester (0.25 g, 0.39 mmol) was treated with 4 M HCl in 1,4-dioxane (0.098 mL, 0.39 mmol) for 1 h. The reaction mixture was then concentrated to yield the product. LCMS calculated for C ₂₉ H ₂₉ N ₈ O ₃ (M+H) ⁺ : m/z = 537.2. Experimental value: 537.2. Step 7 : N-(4-(4- amino- 7-(1-( cyclopropanecarbonyl ) azetidin -3- yl ) pyrrolo [1,2-f][1,2,4] Triazin -5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -(4-(4-amino-7-(azetidin-3-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl )-1-isopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-methamide (0.0055g, 10.3 µmol) and Et ₃ N To a mixture of CH ₂ Cl ₂ (1 ml) was added cyclopropanecarbonyl chloride (1.3 mg, 0.012 mmol). The reaction mixture was stirred at room temperature for 1 h, concentrated and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₃ H ₃₃ N ₈ O ₄ (M+H) ⁺ : m/z = 605.3. Experimental value: 605.2. Example 95. N -(4-(4- amino- 7-( morpholinylmethyl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )- 1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : 4- Aminopyrrolo [1,2-f][1,2,4] triazine -7- carbaldehyde

To a solution of pyrrolo[2,1- f ][1,2,4]triazin-4-amine (1.0 g, 7.45 mmol) in DMF (15 mL) at 0 °C was added POCl ₃ (3.47 mL , 37.3 mmol). The reaction mixture was then stirred at 60°C overnight, cooled to room temperature, quenched with saturated _NaHCO solution and extracted with EtOAc (30 mL×3). The combined organic layers were washed with _brine , dried over _Na2SO4 , concentrated and purified via column chromatography (0% to 15% MeOH _{in CH2Cl2} ) to give the product (200 mg, 16%). LCMS calculated for C ₇ H ₇ N ₄ O (M+H) ⁺ : m/z = 163.1. Experimental value: 163.1. Step 2 : 4- Amino -5- bromopyrrolo [1,2-f][1,2,4] triazine -7- carbaldehyde

To a solution of 4-aminopyrrolo[2,1- f ][1,2,4]triazine-7-carbaldehyde (200 mg, 1.23 mmol) in THF (6.0 ml) was added portionwise at room temperature. 1,3-Dibromo-5,5-dimethylhydantoin (212 mg, 0.74 mmol) was added. The reaction mixture was then stirred at room temperature for 1 h and diluted with water (30 mL)/EtOAc (30 mL). The organic layer was separated, washed with _brine , dried over _Na2SO4 and concentrated to give product (127 mg, 43%) which was used directly in the next step. LCMS calculated for C ₇ H ₆ BrN ₄ O (M+H) ⁺ : m/z = 241.0. Experimental value: 241.0. Step 3 : N-(4-(4- amino -7- formylpyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl 2,4- dioxy -3- phenyl - 1,2,3,4- tetrahydropyrimidine -5- methamide

4-Amino-5-bromopyrrolo[2,1- f ][1,2,4]triazine-7-carbaldehyde (126 mg, 0.52 mmol), 1-isopropyl-2,4-di Pendant oxy-3-phenyl- N- (4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)phenyl)-1,2 , 3,4-tetrahydropyrimidine-5-carboxamide (248 mg, 0.52 mmol) (from Example 61, step 5), chloro(2-dicyclohexylphosphino-2',4',6'-tri Isopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G2) (41 mg, 0.052 mmol) and Na ₂ A mixture of CO ₃ (111 mg, 1.04 mmol) in 1,4-dioxane (4.0 mL)/water (1.0 mL) was purged with N ₂ and stirred at 70 °C for 2 h. The reaction mixture was then cooled to room temperature and diluted with water (30 mL)/EtOAc (30 mL). The organic layer was separated, washed with _brine , dried over _Na2SO4 , concentrated and purified via column chromatography (0% to 15% MeOH _{in CH2Cl2} ) to give the product (266 mg, 100%). LCMS calculated for C ₂₇ H ₂₄ N ₇ O ₄ (M+H) ⁺ : m/z = 510.2. Experimental value: 510.2. Step 4 : N-(4-(4- amino- 7-( morpholinylmethyl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl )- 1- isopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To N -(4-(4-amino-7-methanoylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl)-1- at room temperature Isopropyl-2,4-dioxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-methamide (20 mg, 0.039 mmol), morpholine (0.017 mL, 0.20 mmol) and acetic acid (0.011 mL, 0.20 mmol) in _ClCH2CH2Cl ( _1.5 mL) was added sodium triacetyloxyborohydride (42 mg, 0.20 mmol). The reaction mixture was then stirred at 50°C for 15 min, cooled to room temperature, concentrated, diluted with MeOH and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product (TFA salt) as a white solid ). LCMS calculated for C ₃₁ H ₃₃ N ₈ O ₄ (M+H) ⁺ : m/z = 581.3. Experimental value: 581.3. Example 96. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin -5- yl ) phenyl )-2- isopropyl -3,5- bisoxy -4- phenyl -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carboxamide Step 1 : N- Phenylhydrazinemethionamide

To a stirred solution of hydrazine hydrate (1.7 g, 34 mmol) in isopropyl alcohol (300 mL) was added benzene isothiocyanate (3.4 mL) at room temperature. The reaction mixture was stirred at room temperature for 30 min and the resulting solid was collected by filtration, washed with isopropyl alcohol and dried to give the product (4.8 g). LCMS calculated value for C ₇ H ₁₀ N ₃ S (M+H) ⁺ : m/z = 168.1. Experimental value: 168.1. Step 2 : 5 - Penyloxy -4- phenyl -3- thione -2,3,4,5 - tetrahydro -1,2,4- triazine - 6- carboxylic acid ethyl ester

A mixture of diethyl pendant oxymalonate (5.0 mL, 33 mmol) and N -phenylhydrazinemethionate (5.5 g, 33 mmol) in EtOH (100 mL) was refluxed for 3 days. The reaction mixture was cooled to room temperature and the resulting solid was collected by filtration, washed with cold EtOH and dried to give product (6 g, 66%). LCMS calculated value for C ₁₂ H ₁₂ N ₃ O ₃ S (M+H) ⁺ : m/z = 278.1. Experimental value: 278.2. Step 3 : Ethyl 3,5- bisoxy -4- phenyl -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carboxylate

5-Pendantoxy-4-phenyl-3-thione-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (6.0 g, 22 mmol) A mixture of , H ₂ O ₂ (30 wt% in water, 6.4 mL) and acetic acid (20 mL) in DMF (60 mL) was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with water, brine, dried and concentrated. The resulting solid was triturated with diethyl ether to give the product. LCMS calculated for C ₁₂ H ₁₂ N ₃ O ₄ (M+H) ⁺ : m/z = 262.1. Experimental value: 262.2. Step 4 : ethyl 2- isopropyl -3,5- bisoxy -4- phenyl -2,3,4,5 - tetrahydro -1,2,4- triazine -6 -carboxylate

To ethyl 3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylate (0.6 g, 2 mmol) and K ₂ To a mixture of CO ₃ (0.95 g, 6.9 mmol) in DMF (7 mL) was added 2-iodopropane (0.46 mL, 4.6 mmol). The reaction mixture was stirred at 65 °C for 2 h, cooled to room temperature, diluted with EtOAc and washed with saturated _NaHCO solution, water and brine. The organic layer was separated, dried over _Na2SO4 and concentrated to provide _the product. LCMS calculated for C ₁₅ H ₁₈ N ₃ O ₄ (M+H) ⁺ : m/z = 304.1. Experimental value: 304.1. Step 5 : 2- isopropyl -3,5- bisoxy -4- phenyl -2,3,4,5- tetrahydro -1,2,4- triazine -6- carboxylic acid

2-Isopropyl-3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-carboxylic acid ethyl ester (1.0 g, A mixture of 3.4 mmol) and water (1.0 mL) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 70 °C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The combined organic layers were dried over _MgSO4 and concentrated to provide the desired product. LCMS calculated for C ₁₃ H ₁₄ N ₃ O ₄ (M+H) ⁺ : m/z = 276.1. Experimental value: 276.0. Step 6 : 4-[4-Amino-5-(4-{[(2-isopropyl-3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro- 1,2,4-triazin-6-yl)carbonyl]amino}phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid 3rd butyl ester

To 4-[4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid tertiary Butyl ester (150 mg, 0.37 mmol) (from Example 107, Step 4) and 2-isopropyl-3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro-1 To a mixture of 2,4-triazine-6-carboxylic acid (101 mg, 0.37 mmol) in DMF (1.7 mL) was added Et ₃ N (77 μL, 0.55 mmol), followed by HATU (0.168 g, 0.44 mmol). . The reaction mixture was stirred at room temperature for 1 h, quenched with water and the resulting solid was collected by filtration and dried to yield the product (0.2 g, 80%). LCMS calculated for C ₃₅ H ₄₀ N ₉ O ₅ (M+H) ⁺ : m/z = 666.3. Experimental value: 666.2. Step 7 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -2- isopropyl -3,5- bisoxy -4- phenyl -2,3,4,5 - tetrahydro -1,2,4- triazine -6- methamide

To 4-[4-amino-5-(4-{[(2-isopropyl-3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro-1, 2,4-Triazin-6-yl)carbonyl]amino}phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid tertiary To a mixture of butyl ester (0.20 g, 0.30 mmol) in _CH2Cl2 (0.47 mL) was added 4 M HCl in 1,4 _- dioxane (0.71 mL, 2.8 mmol). The mixture was stirred at room temperature for 1 h and concentrated to give product (0.17 g, 100%). LCMS calculated for C ₃₀ H ₃₂ N ₉ O ₃ (M+H) ⁺ : m/z = 566.3. Experimental value: 566.2. Step 8 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-2- isopropyl -3,5- bisoxy -4- phenyl -2,3,4,5 - tetrahydro -1,2,4- triazine -6- carboxamide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl]-2-iso Propyl-3,5-bisoxy-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazine-6-methamide (20 mg, 0.03 mmol) and To a solution _{of Et3N} (24 μL, 0.17 mmol) in _CH2Cl2 (1.1 mL) was added isobutyryl chloride (0.0044 g, 0.041 mmol). The reaction mixture was stirred at room temperature for 4 h and purified directly via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₄ H ₃₈ N ₉ O ₄ (M+H) ⁺ : m/z = 636.3. Experimental value: 636.3. Example 97. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -6- methyl -5-(1- methyl - 1H - pyrazol -5- yl )-4- side oxy -1,4- dihydropyridine -3 -Formamide _ Step 1 : (E/Z)-3-(( dimethylamino ) methylene )-6- methyl -2H- pyran -2,4(3H) -dione

To a solution of 6-methyl- 2H -piran-2,4( 3H )-dione (13 g, 103 mmol) in toluene (30 mL) was added N,N -dimethylformamide Dimethylacetal (15 ml, 113 mmol). The resulting solution was stirred at room temperature for 36 h and concentrated to yield a red solid, which was used directly in the next step. LCMS calculated for C ₉ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 182.1. Experimental value: 182.1. Step 2 : 1- isopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

Add ( E/Z )-3-((dimethylamino)methylene)-6-methyl- 2H -pyran-2,4( 3H )-dione ( 2.0 g, 11.0 mmol), propyl-2-amine (1.41 mL, 16.6 mmol), and sodium tert-butoxide (1.57 g, 16.3 mmol) in EtOH (80 mL). The round bottom was equipped with an air condenser and the resulting mixture was stirred at 90 °C for 18 h, cooled to room temperature, concentrated and _treated with water and _CH2Cl2 . After the solution was acidified _with 4 N HCl solution and separated, the aqueous layer was extracted with _CH2Cl2 . The combined organic layers were washed with water, brine, dried _{over Na2SO4} and concentrated to give crude product which was used directly in the next step. LCMS calculated for C ₁₀ H ₁₄ NO ₃ (M+H) ⁺ : m/z = 196.1. Experimental value: 196.1. Step 3 : 5- Bromo -1- isopropyl -6- methyl - 4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

To a solution of 1-isopropyl-6-methyl-4-pendantoxy-1,4-dihydropyridine-3-carboxylic acid (219 mg, 1.12 mmol) in DCE (5 mL) was added NBS (295 mg, 1.66 mmol) and the resulting solution was stirred at room temperature overnight, diluted with water and after separation, the _aqueous layer was extracted with _CH2Cl2 . The combined organic layers were washed with water, brine, dried _{over Na2SO4} and concentrated to give crude product which was used directly in the next step. LCMS calculated for C ₁₀ H ₁₃ BrNO ₃ (M+H) ⁺ : m/z = 274.0. Experimental value: 274.0. Step 4 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -1- isopropyl -6- methyl - 4- sideoxy -1,4- dihydropyridine -3- methamide

To 5-bromo-1-isopropyl-6-methyl-4-pendantoxy-1,4-dihydropyridine-3-carboxylic acid (154 mg, 0.56 mmol) and HATU (256 mg, 0.67 mmol) in To a solution in DCE (5 mL) was added DIPEA (0.24 mL, 1.41 mmol) and 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][ 1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (213 mg, 0.56 mmol) (from Example 83, Step 2). The resulting solution was stirred at room temperature overnight and purified via column chromatography (0% to 100% EtOAc in hexanes) to yield the product. LCMS calculated for C ₃₁ H ₃₇ BrN ₇ O ₃ (M+H) ⁺ : m/z = 634.2. Experimental value: 634.2. Step 5 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl )-1- isopropyl -6- methyl -5-(1- methyl -1H- pyrazol -5- yl )-4- side oxy -1,4- dihydropyridine -3- Formamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (62 mg, 0.098 mmol), (1-methyl -1H -pyrazol-5-yl)boronic acid (61.5 mg, 0.489 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-dihydrochloride) Benzene) (2'-amino-1,1'-biphenyl-2-yl)palladium(II) (Xphos Pd G2) (11.53 mg, 0.015 mmol) and tripotassium phosphate (0.024 ml, 0.29 mmol) in 1 A mixture of 4-dioxane (2.0 ml) and water (0.40 ml) was degassed and purged with _N2 several times before heating in a sealed vial at 90°C overnight. After cooling to room temperature, the mixture was diluted with MeOH, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₅ H ₄₂ N ₉ O ₃ (M+H) ⁺ : m/z = 636.3. Experimental value: 636.4. ¹ H NMR (600 MHz, DMSO) δ 12.87 (s, 1H), 8.73 (s, 1H), 8.06 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 1.8 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 6.73 (s, 1H), 6.21 (d, J = 1.8 Hz, 1H), 4.85-4.76 (m, 1H), 4.55 (d, J = 12.9 Hz, 1H), 4.08 (d, J = 13.1 Hz, 1H), 3.61 (s, 3H), 3.42 (dd, J = 11.9, 3.7 Hz, 1H), 3.28-3.16 (m, 1H), 2.98 -2.86 (m, 1H), 2.77-2.64 (m, 1H), 2.33 (s, 3H), 2.13-1.96 (m, 2H), 1.71-1.58 (m, 1H), 1.58-1.47 (m, 7H) , 1.08-0.97 (m, 6H). Example 98. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-5'- fluoro -1- isopropyl -2- methyl -4- sideoxy -1,4- dihydro- [3,3'- bipyridyl ]-5- methamide

This compound was prepared according to a synthetic sequence similar to Example 97, using (5-fluoropyridin-3-yl)boronic acid instead of (1-methyl-1 H -pyrazol-5-yl)boronic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₆ H ₄₀ FN ₈ O ₃ (M+H) ⁺ : m/z = 651.3. Experimental value: 651.3. ¹ H NMR (500 MHz, DMSO) δ 12.86 (s, 1H), 8.74 (s, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.34 (m, 1H), 8.08 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.71 (m, 1H), 7.47 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.83 (m, 1H), 4.56 (m, 1H ), 4.09 (m, 1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.91 (m, 1H), 2.70 (m, 1H), 2.34 (s, 3H), 2.02 (m, 2H) , 1.64 (m, 1H), 1.53 (m, 7H), 1.02 (m, 6H). Example 99. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ) phenyl )-5-(3- cyanophenyl )-1- isopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- methamide

This compound was prepared according to a synthetic sequence similar to Example 97, using (3-cyanophenyl)boronic acid instead of (1-methyl- 1H -pyrazol-5-yl)boronic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₈ H ₄₁ N ₈ O ₃ : m/z = 657.3; experimental value: 657.3. ¹ H NMR (500 MHz, DMSO) δ 12.91 (s, 1H), 8.73 (s, 1H), 8.08 (s, 1H), 7.87 (m, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.74 (m, 1H), 7.69 (m, 1H), 7.61 (m, 1H), 7.46 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.81 (m, 1H), 4.55 (m , 1H), 4.08 (m, 1H), 3.42 (m, 1H), 3.21 (m, 1H), 2.90 (m, 1H), 2.77-2.61 (m, 1H), 2.30 (s, 3H), 2.13- 1.89 (m, 2H), 1.65 (m, 1H), 1.52 (m, 7H), 1.02 (m, 6H). Example 100. N -(4-(4- Amino -6- bromo -7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazine -5- yl ) phenyl )-4- methoxy -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 4- Methoxy -2 -Pendantoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

4-Methoxy-2-pendantoxy-1,2-dihydropyridine-3-carboxylic acid (1.40 g, 8.28 mmol) (from Enamine Ltd.), phenylboronic acid (4.04 g, 33.1 mmol), activated 4Å A mixture of molecular sieves ₍ 2.59 g) and copper(II) acetate (4.51 g, 24.8 mmol) in _CH2Cl2 (50 mL) was treated with pyridine (2.68 mL) and stirred at room temperature for 3 days. The reaction mixture was then diluted with MeOH, filtered, concentrated and purified via column chromatography (0% to 100% MeOH in EtOAc) to yield the product as a light green powder (244 mg, 12%). LCMS calculated for C ₁₃ H ₁₂ NO ₄ (M+H) ⁺ : m/z = 246.1. Experimental value: 246.1. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-4- methoxy -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

To 4-methoxy-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (35 mg, 0.14 mmol) and 1-(4-(4-amino-5- (4-Aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (59.4 mg, 0.16 mmol) (from Example 83, step 2) To a mixture in DMF (571 µL) was added Et ₃ N (60 µL) followed by HATU (109 mg, 0.29 mmol). The resulting mixture was stirred at room temperature for 30 min, filtered and the crude material was purified via column chromatography (0% to 30% MeOH in EtOAc) to yield the desired product as a pale yellow powder (70 mg, 81%) . LCMS calculated for C ₃₄ H ₃₆ N ₇ O ₄ (M+H) ⁺ : m/z = 606.3. Experimental value: 606.3. Step 3 : N-(4-(4- amino -6- bromo -7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazine -5- yl ) phenyl )-4- methoxy -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (61 mg, 0.10 mmol) in DMF (403 µL) Add NBS (19 mg, 0.11 mmol). The resulting mixture was stirred at room temperature for 5 min, diluted with EtOAc/THF, filtered, washed with saturated _NaHCO3 solution, water, brine, dried over _Na2SO4 and _concentrated . The crude material was purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to give the product as a creamy white powder. LCMS calculated for C ₃₄ H ₃₅ BrN ₇ O ₄ (M+H) ⁺ : m/z = 684.2. Experimental value: 684.2. Example 101. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-5- bromo -1-(5- fluoropyridin -3- yl )-6- methyl -2- sideoxy -1,2- dihydropyridine -3- methamide Step 1 : 5- Bromo -5'- fluoro -6- methyl -2- sideoxy -2H-[1,3'- bipyridine ]-3- carboxylic acid

5-Bromo-5'-fluoro-6-methyl-2-pendantoxy- 2H- [1,3'-bipyridyl]-3-carboxylic acid ethyl ester (1.0 g, 2.82 mmol) (from Affinity Research Chemicals) were dissolved in THF (10 mL) and ethanol (6.7 mL). The mixture was then treated with 1 M NaOH in water (11 mL) and the reaction mixture was stirred at 25°C for 20 min. The resulting mixture was neutralized to pH 6-7 with 12 M HCl solution and the organic solvent was removed under vacuum. The resulting mixture was extracted with EtOAc. The combined organic layers were dried and concentrated to yield the product as a light brown powder (975 mg). LCMS calculated for C ₁₂ H ₉ BrFN ₂ O ₃ (M+H) ⁺ : m/z = 327.0. Experimental value: 327.0. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -5'- fluoro -6- methyl -2- sideoxy -2H-[1,3'- bipyridyl ]-3- methamide

To 5-bromo-5'-fluoro-6-methyl-2-pendantoxy- 2H- [1,3'-bipyridine]-3-carboxylic acid (38 mg, 0.069 mmol) and 1-(4- (4-Amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methyl To a mixture of propan-1-one (25 mg, 0.066 mmol) (from Example 83, step 2) in DMF (264 µL) was added Et ₃ N (28 µL), followed by HATU (50 mg, 0.13 mmol). . The resulting mixture was stirred at room temperature for 20 min and the crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a creamy white powder (TFA salt). LCMS calculated for C ₃₃ H ₃₃ BrFN ₈ O ₃ (M+H) ⁺ : m/z = 687.2. Experimental value: 687.2. ¹ H NMR (600 MHz, DMSO) δ 11.64 (s, 1H), 8.84 (d, J = 2.6 Hz, 1H), 8.62 (d, J = 12.6 Hz, 2H), 8.12 (dt, J = 9.2, 2.3 Hz, 1H), 8.06 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.73 (s, 1H), 4.55 (d, J = 12.6 Hz, 1H), 4.07 (d, J = 14.0 Hz, 1H), 3.42 (tt, J = 12.0, 3.5 Hz, 1H), 3.21 (t, J = 12.9 Hz, 1H), 2.91 (dt, J = 13.5 , 6.7 Hz, 1H), 2.75-2.66 (m, 2H), 2.25 (s, 3H), 2.04 (dd, J = 30.5, 13.5 Hz, 2H), 1.72 (m, 1H), 1.60 (m, 1H) , 1.52 (d, J = 12.1 Hz, 1H), 1.05-0.99 (m, 6H). Example 102. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5-( cyanomethyl )-5'- fluoro -6- methyl -2- sideoxy - 2H- [1,3'- bipyridyl ]-3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene methyl)-5-bromo-5'-fluoro-6-methyl-2-pendantoxy- 2H- [1,3'-bipyridyl]-3-methamide (8.0 mg, 0.012 mmol) (from Example 101, step 2), isoxazol-4-ylboronic acid (2.0 mg, 0.02 mmol), 1,4-dioxane (200 µL), N -ethyl- N -isopropylpropan-2-amine Pd( t Bu ₃ ) ₂ (3.0 mg, 5.8 µmol) was added to a stirred mixture of (4.5 mL) and water (40 µL). The reaction mixture was then heated at 110°C for 60 min, cooled to room temperature, diluted with DMF and purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to yield the product as a creamy white powder. LCMS calculated for C ₃₅ H ₃₅ FN ₉ O ₃ (M+H) ⁺ : m/z = 648.3. Experimental value: 648.3. Example 103. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5'- fluoro -6- methyl -2- sideoxy -5-( thiazol- 4- yl )-2 H -[1,3'- bipyridyl ]-3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene methyl)-5-bromo-5'-fluoro-6-methyl-2-side oxy- 2H- [1,3'-bipyridyl]-3-methamide (8.0 mg, 0.012 mmol) and Pd To a mixture of (Ph ₃ P) ₄ (2.7 mg, 2.3 µmol) in toluene (0.30 mL) was added 4-(tributylstannyl)thiazole (8.7 mg, 0.023 mmol). The reaction mixture was sealed in a microwave vial, evacuated and backfilled with _N2 several times and heated at 120 °C for 20 h. The reaction mixture was cooled to room temperature and the crude material was purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to give the product as a creamy white powder. LCMS calculated value for C ₃₆ H ₃₅ FN ₉ O ₃ S (M+H) ⁺ : m/z = 692.3. Experimental value: 692.3. Example 104. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- side oxy -1- phenyl -1,6- dihydro- [2,2'- bipyridyl ]-5- methamide Step 1 : 6- Penyloxy -1- phenyl -1,6- dihydro- [2,2'- bipyridyl ]-5- carbonitrile

2-cyano- N -phenylacetamide (1.60 g, 10.0 mmol), 3-(dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one (1.94 g, 11.0 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.98 mL, 10.0 mmol) in EtOH (20 mL) was heated at 90 °C overnight. After cooling to room temperature, _the reaction mixture was concentrated and partitioned between _CH2Cl2 (60 mL) and 2 M HCl solution (20 mL). The organic layer was separated, washed with water, dried over _MgSO4 , concentrated and purified via column chromatography (20% to 100% EtOAc in hexane) to give the product (1.25 g, 46%). LCMS calculated for C ₁₇ H ₁₂ N ₃ O (M+H) ⁺ : m/z = 274.1. Experimental value: 274.2. Step 2 : 6- Pendant oxy -1- phenyl -1,6- dihydro- [2,2'- bipyridine ]-5- carboxylic acid

Dissolve 6-Pendantoxy-1-phenyl-1,6-dihydro-[2,2'-bipyridyl]-5-carbonitrile (0.20) in concentrated sulfuric acid (1.5 mL) and water (1.5 mL). g, 0.73 mmol) and heated at 120°C for 3 h. After cooling to room temperature, the reaction mixture was carefully neutralized to pH approximately 7 with 10% NaOH solution at 0°C. The resulting mixture was extracted with 9:1 _CH2Cl2 /MeOH (5 mL×3) and the combined organic layers were dried over _Na2SO4 and concentrated to give _crude product (0.19 g, 89% ₎ , which was used directly In the next step. LCMS calculated for C ₁₇ H ₁₃ N ₂ O ₃ (M+H) ⁺ : m/z = 293.1. Experimental value: 293.1. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-6- side oxy -1- phenyl -1,6- dihydro- [2,2'- bipyridyl ]-5- methamide

To 6-Pendantoxy-1-phenyl-1,6-dihydro-[2,2'-bipyridine]-5-carboxylic acid (0.015 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (3 mL), 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazine-7 was added -(yl)piperidin-1-yl)-2-methylpropan-1-one (0.019 g, 0.0500 mmol) (from Example 83, step 2) and _Et3N (0.021 ml, 0.15 mmol). The mixture was stirred at room temperature until complete, diluted with MeOH, adjusted to pH ~2 with TFA and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₈ H ₃₇ N ₈ O ₃ (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. Example 105. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6'- methyl -6- sideoxy -1- phenyl -1,6- dihydro- [2,3'- bipyridyl ]-5- methamide Step 1 : 3-( dimethylamino )-1-(6- methylpyridin -3- yl ) prop -2- en -1- one

1-(6-methylpyridin-3-yl)ethan-1-one (2.50 g, 18.5 mmol) and 1,1-dimethoxy- N , N -dimethylmethylamine (4.41 g, 37.0 mmol) was heated at 100°C for 8 h, cooled to room temperature and concentrated. The resulting residue was triturated with diethyl ether. The solid was then collected by filtration and washed with diethyl ether to yield crude product (2.75 g, 78%). LCMS calculated for C ₁₁ H ₁₅ N ₂ O (M+H) ⁺ : m/z = 191.1. Experimental value: 191.1. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-6'- methyl -6- sideoxy -1- phenyl -1,6- dihydro- [2,3'- bipyridyl ]-5- methamide

According to the synthetic sequence similar to step 1 to step 3 of Example 104, 3-(dimethylamino)-1-(6-methylpyridin-3-yl)prop-2-en-1-one was used instead of 3-( This compound was prepared by dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₉ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 667.3. Experimental value: 667.3. Example 106. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-3- methyl -6- sideoxy -1- phenyl- 1,6- dihydro- [2,3'- bipyridyl ]-5- methamide Step 1 : 3-( dimethylamino )-2- methyl -1-( pyridin -3- yl ) prop -2- en -1- one

This compound was prepared according to a synthetic sequence similar to Example 105 step 1, using 1-(pyridin-3-yl)propan-1-one instead of 1-(6-methylpyridin-3-yl)ethan-1-one. LCMS calculated for C ₁₁ H ₁₅ N ₂ O (M+H) ⁺ : m/z = 191.1. Experimental value: 191.1. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-3- methyl -6- sideoxy -1- phenyl- 1,6- dihydro- [2,3'- bipyridyl ]-5- methamide

According to the synthetic sequence similar to step 1 to step 3 of Example 104, 3-(dimethylamino)-2-methyl-1-(pyridin-3-yl)prop-2-en-1-one was used instead of 3- (Dimethylamino)-1-(pyridin-2-yl)prop-2-en-1-one was used to prepare this compound. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₉ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 667.3. Experimental value: 667.3. Example 107. N -{4-[4- Amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -5-(1- methyl - 1H - pyrazol -4- yl )-2- side oxy -1- phenyl -1,2- dihydropyridine -3- Formamide Step 1 : 6- Methyl -2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- carbonitrile

To 2-cyano- N -phenylacetamide (5.0 g, 31.2 mmol) and 4-methoxy-3-buten-2-one (6.2 g, 62 mmol) in 2-(2-methoxy To a mixture of ethanol (75 mL) was added DABCO (3.50 g, 31.2 mmol). The _resulting mixture was stirred at 120°C overnight, cooled to room temperature, concentrated and the material partitioned between _CH2Cl2 (300 mL) and 2 M HCl solution (100 mL). The organic layer was separated, washed with water, dried over _MgSO4 , concentrated and EtOAc was added. The mixture was stirred for 30 min and the resulting solid was collected by filtration and dried to give the product (3.17 g). The filtrate was concentrated and purified via column chromatography (20% to 90% EtOAc in hexane) to yield an additional 1.58 g of product as a brown solid (72% combined). LCMS calculated value for C ₁₃ H ₁₁ N ₂ O (M+H) ⁺ : m/z = 211.1. Experimental value: 211.1. Step 2 : 6- Methyl -2- Pendantoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

6-Methyl-2-sideoxy-1-phenyl-1,2-dihydropyridine-3-carbonitrile (3.17 g, 15.1 mmol) and KOH (3.47 g, 61.8 mmol) were dissolved in EtOH (34 mL )/water (8.0 mL) was stirred at 90 °C for 46 h. The EtOH was evaporated and the resulting mixture was diluted with water and _washed with _CH2Cl2 . The aqueous layer was then acidified _with 2 N HCl solution and extracted with _CH2Cl2 . The combined organic layers were dried over _MgSO4 and concentrated to give the product (2.2 g, 64%). LCMS calculated for C ₁₃ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 230.1. Experimental value: 230.1. Step 3 : 5- bromo -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

To a solution of 6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (2.20 g, 9.6 mmol) in DMF (30 mL) was added NBS (1.70 g , 9.55 mmol). The reaction mixture was stirred at room temperature for 4 h, more NBS (300 mg) was added and stirred overnight. Water (100 mL) was then added to the reaction mixture at 0°C and stirring was continued for 20 min. The resulting solid was collected by filtration, washed with water and dried to yield the product as a tan solid (2.4 g, 81%). LCMS calculated value for C ₁₃ H ₁₁ BrNO ₃ (M+H) ⁺ : m/z = 308.0. Experimental value: 308.0. Step 4 : 4-[4- Amino- 5-(4- aminophenyl ) pyrrolo [2,1-f][1,2,4] triazin -7- yl ] piperidine -1- carboxylic acid 3rd butyl ester

4-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (400 mg, 1 mmol) (from Example 32, Step 3), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (265 mg, 1.21 mmol) , Dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) ( A mixture of 39.7 mg, 0.051 mmol) and potassium phosphate (643 mg, 3.03 mmol) in 1,4-dioxane (9 mL)/water (1.6 mL) was degassed with _N and then stirred at 90 °C overnight. . The reaction mixture was cooled to room temperature, diluted with EtOAc, filtered through celite, concentrated and purified via column chromatography (10% to 100% EtOAc in hexanes, followed by 10% MeOH in EtOAc) to yield the product ( 200 mg, 50%). LCMS calculated for C ₂₂ H ₂₉ N ₆ O ₂ (M+H) ⁺ : m/z = 409.2. Experimental value: 409.2. Step 5 : 4-[4- Amino- 5-(4-{[(5- bromo -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridin -3- yl ) carbonyl ] amino } phenyl ) pyrrolo [2,1-f][1,2,4] triazin -7- yl ] piperidine -1- carboxylic acid tert-butyl ester

To 4-[4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid tertiary Butyl ester (100 mg, 0.25 mmol) and 5-bromo-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (75 mg, 0.25 mmol) in DMF To the mixture in (1.5 mL) was added Et ₃ N (51 uL, 0.37 mmol), followed by HATU (112 mg, 0.29 mmol). The resulting mixture was stirred at room temperature overnight, water was added and extracted with EtOAc. The combined organic layers were dried over _Na2SO4 , concentrated and purified via column chromatography (10% to 80% EtOAc in hexanes, followed by 10% MeOH _in EtOAc) to yield the product (95 mg, 56%) . LCMS calculated for C ₃₅ H ₃₇ BrN ₇ O ₄ (M+H) ⁺ : m/z = 698.2. Experimental value: 698.3. Step 6 : 4-{4- amino -5-[4-({[6- methyl -5-(1- methyl -1H- pyrazol -4- yl )-2- side oxy -1- Phenyl -1,2- dihydropyridin -3- yl ] carbonyl } amino ) phenyl ] pyrrolo [2,1-f][1,2,4] triazin -7- yl } piperidine -1 -Tertiary butyl formate

4-[4-Amino-5-(4-{[(5-bromo-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl ]Amino}phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid tert-butyl ester (95 mg, 0.14 mmol), 1- Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl) -1H -pyrazole (34.0 mg, 0.16 mmol), bicyclo Hexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (5.3 mg, A mixture of 0.0068 mmol) and potassium phosphate (87 mg, 0.41 mmol) in 1,4-dioxane (1.3 mL)/water (0.30 mL) was degassed with _N2 and stirred at 90 °C for 3 h. The resulting mixture was cooled to room temperature, diluted with _{CH2Cl2 /} water and filtered through celite. The organic layer was separated and concentrated to give crude product (88 mg), which was used directly in the next step. LCMS calculated for C ₃₉ H ₄₂ N ₉ O ₄ (M+H) ⁺ : m/z = 700.3. Experimental value: 700.4. Step 7 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -6- Methyl -5-(1- methyl -1H- pyrazol -4- yl )-2- side oxy -1- phenyl -1,2- dihydropyridine - 3-methamide

To 4-{4-amino-5-[4-({[6-methyl-5-(1-methyl-1 H -pyrazol-4-yl)-2-pendantoxy-1-benzene base-1,2-dihydropyridin-3-yl]carbonyl}amino)phenyl]pyrrolo[2,1- f ][1,2,4]triazin-7-yl}piperidine-1- To a solution of tert-butyl formate (87 mg, 0.12 mmol) in _{CH2Cl2 (} 2 mL) was added TFA (1 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated and dried to yield the product as a TFA salt (90 mg). LCMS calculated value (M+H) ⁺ for C ₃₄ H ₃₄ N ₉ O ₂ : m/z = 600.3; experimental value: 600.2. Step 8 : N-{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -5-(1- methyl -1H- pyrazol -4- yl )-2- side oxy -1- phenyl -1,2- dihydropyridine -3- methyl amide

To N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl]-6-methyl Phyl-5-(1-methyl- 1H -pyrazol-4-yl)-2-side-oxy-1-phenyl-1,2-dihydropyridine-3-carboxamide (60 mg, 0.084 To a mixture of Et ₃ N (59 uL, 0.42 mmol) in CH ₂ Cl ₂ (1 mL) was added isobutyryl chloride (12 uL, 0.11 mmol). The resulting mixture was stirred at room temperature for 90 min and purified directly via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₈ H ₄₀ N ₉ O ₃ : m/z = 670.3; experimental value: 670.2. ¹ H NMR (600 MHz, DMSO) δ 12.05 (s, 1H), 8.46 (s, 1H), 8.01 (s, 1H), 7.97 (s, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.64-7.59 (m, 3H), 7.57-7.52 (m, 1H), 7.45-7.41 (m, 4H), 6.69 (s, 1H), 4.53 (d, J = 12.3 Hz, 1H), 4.05 (d, J = 12.9 Hz, 1H), 3.89 (s, 3H), 3.43-3.34 (m, 1H), 3.24-3.15 (m, 1H), 2.89 (hept, J = 6.7 Hz, 1H), 2.68 (t, J = 12.0 Hz, 1H), 2.09 (s, 3H), 2.02 (dd, J = 32.4, 13.2 Hz, 2H), 1.56 (dd, J = 72.6, 9.9 Hz, 2H), 1.03-0.97 (m, 6H) . Example 108. N -{4-[4- Amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -2- side oxy -1- phenyl -5- pyrimidin -2- yl -1,2- dihydropyridine -3- methamide Step 1 : 5- Bromo -6- methyl -2- side-oxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid ethyl ester

5-Bromo-6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (1.0 g, 3.24 mmol) (Example 107, step 3) and sulfuric acid (180 A mixture of uL, 3.4 mmol) in EtOH (60 mL) was refluxed for 3 days, cooled to room temperature and concentrated. The resulting residue was dissolved _{in CH2Cl2} , washed with saturated _NaHCO3 solution, dried over _MgSO4 and concentrated to give the product as a brown solid (1 g). LCMS calculated value (M+H) ⁺ for C ₁₅ H ₁₅ BrNO ₃ : m/z = 336.0; experimental value: 336.1. Step 2 : 6- methyl -2- side oxy -1- phenyl -5-(4,4,5,5- tetramethyl -1,3,2- dioxaboropentan -2- yl ) -Ethyl 1,2- dihydropyridine -3- carboxylate

5-Bromo-6-methyl-2-side-oxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (520 mg, 1.5 mmol), 4,4,5,5, 4',4',5',5'-octamethyl-[2,2']bi[[1,3,2]dioxaboropentyl] (786 mg, 3.09 mmol), [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (57 mg, 0.077 mmol) and potassium acetate (455 mg, 4.64 mmol) in 1,4-dioxane (13 mL) The mixture was degassed with _N2 for 5 min and then stirred at 90 °C for 17 h, cooled to room temperature and filtered through a plug of celite (washed with EtOAc). The filtrate was washed with _brine , dried over _Na2SO4 and concentrated. The crude material was purified via column chromatography (15% to 65% EtOAc in hexane) to yield product (168 mg, 28%). LCMS calculated value (M+H) ⁺ for C ₂₁ H ₂₇ BNO ₅ : m/z = 384.2; experimental value: 384.2. Step 3 : 6- Methyl -2- side-oxy -1- phenyl -5- pyrimidin -2- yl -1,2- dihydropyridine -3- carboxylate ethyl ester

In a sealed microwave vial, add 6-methyl-2-pentoxy-1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentane -2-yl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester (168 mg, 0.44 mmol), 2-bromopyrimidine (83.6 mg, 0.53 mmol), dicyclohexyl (2',4',6 '-Triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (17 mg, 0.022 mmol) and potassium phosphate (279 mg , 1.32 mmol) in 1,4-dioxane (5 mL)/water (1 mL) was stirred at 90 °C for 2.5 h. The reaction mixture was then cooled to room _temperature , diluted with _CH2Cl2 /water and filtered through celite. The organic layer was separated and concentrated to give crude product (127 mg, 86%), which was used directly in the next step. LCMS calculated value (M+H) ⁺ for C ₁₉ H ₁₈ N ₃ O ₃ : m/z = 336.1; experimental value: 336.1. Step 4 : 6- Methyl -2- Pendantoxy -1- phenyl -5- pyrimidin - 2- yl -1,2- dihydropyridine -3- carboxylic acid

To ethyl 6-methyl-2-pendantoxy-1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylate (127 mg, 0.38 mmol) in MeOH (2 mL )/water (0.4 mL) was added lithium hydroxide monohydrate (79 mg, 1.89 mmol). The resulting mixture was stirred at 40 °C for 3 h and MeOH was evaporated. The mixture was acidified with IN HCl solution and the resulting solid was collected by filtration, washed with water and dried to give the product (80 mg, 70%). LCMS calculated value for C ₁₇ H ₁₄ N ₃ O ₃ (M+H) ⁺ : m/z = 308.1; found value: 308.0. Step 5 : 6- methyl -2- side oxy -1- phenyl -5- pyrimidin -2- yl -N-[4-(4,4,5,5- tetramethyl -1,3,2 -Dioxaboropentan - 2- yl ) phenyl ]-1,2- dihydropyridine -3- methamide

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)aniline (57 mg, 0.26 mmol) and 6-methyl-2-oxygen To a mixture of 1-phenyl-5-pyrimidin-2-yl-1,2-dihydropyridine-3-carboxylic acid (80 mg, 0.3 mmol) in DMF (1.6 mL) was added Et ₃ N (54 uL , 0.390 mmol), followed by the addition of HATU (119 mg, 0.31 mmol). The resulting mixture was stirred at room temperature overnight, water was added and the solid collected by filtration, washed with water and dried to give the product as a white solid (103 mg, 78%). LCMS calculated value (M+H) ⁺ for C ₂₉ H ₃₀ BN ₄ O ₄ : m/z = 509.2; experimental value: 509.2. Step 6 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -6- Methyl -2- Pendantoxy -1- phenyl -5-( pyrimidin -2- yl )-1,2- dihydropyridine -3- methamide

4-(4-Amino-5-bromopyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (21 mg, 0.053 mmol) (from Example 32, step 3), 6-methyl-2-pendantoxy-1-phenyl-5-pyrimidin-2-yl- N- [4-(4,4,5,5-tetrahydrofuran) Methyl-1,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (32 mg, 0.064 mmol), dicyclohexyl (2',4',6'-triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (2.0 mg, 0.0027 mmol) and A mixture of potassium phosphate (34 mg, 0.16 mmol) in 1,4-dioxane (0.65 mL)/water (0.1 mL) was degassed with _N2 and then stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature, diluted with _{CH2Cl2 /} water and filtered through celite. The organic layer was separated, concentrated and _{CH2Cl2 (} 0.4 mL) and 4 M HCl in 1,4-dioxane (120 uL, 0.48 mmol) were added. The resulting mixture was stirred at room temperature overnight and concentrated to give crude product (30 mg), which was used directly in the next step. LCMS calculated value (M+H) ⁺ for C ₃₄ H ₃₂ N ₉ O ₂ : m/z = 598.3; experimental value: 598.2. Step 7 : N-{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -2- side oxy -1- phenyl -5- pyrimidin -2- yl -1,2- dihydropyridine -3- methamide

According to a synthetic sequence similar to Example 107 step 8, use N -(4-(4-amino-7-(piperidin-4-yl)pyrrolo[1,2- f ][1,2,4]tri Replaced by oxazin-5-yl)phenyl)-6-methyl-2-side oxy-1-phenyl-5-(pyrimidin-2-yl)-1,2-dihydropyridine-3-carboxamide N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl]-6-methyl This compound was prepared by -5-(1-methyl- 1H -pyrazol-4-yl)-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₈ H ₃₈ N ₉ O ₃ : m/z = 668.3; experimental value: 668.2. ¹ H NMR (600 MHz, DMSO) δ 11.89 (s, 1H), 9.16 (s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 8.08 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 2H), 7.59-7.53 (m, 1H), 7.51-7.44 (m, 5H), 6.74 (s, 1H), 4.53 (d, J = 12.3 Hz , 1H), 4.06 (d, J = 12.7 Hz, 1H), 3.48-3.33 (m, 1H), 3.19 (t, J = 12.4 Hz, 1H), 2.89 (hept, J = 6.7 Hz, 1H), 2.68 (t, J = 11.9 Hz, 1H), 2.40 (s, 3H), 2.01 (dd, J = 30.0, 12.2 Hz, 2H), 1.56 (dd, J = 74.3, 9.4 Hz, 2H), 1.00 (d, J = 3.9 Hz, 6H). Example 109. N -{4-[4- Amino- 7-(1- methylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin -5- yl ] phenyl }-6- methyl -2- side oxy -1- phenyl -5- pyrimidin -2- yl -1,2- dihydropyridine -3- methamide

5-Bromo-7-(1-methylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-4-amine (from Example 20, Step 3) ( 31 mg, 0.10 mmol), 6-methyl-2-sideoxy-1-phenyl-5-pyrimidin-2-yl- N- [4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaboropentan-2-yl)phenyl]-1,2-dihydropyridine-3-methamide (61 mg, 0.12 mmol), dicyclohexyl (2',4', 6'-Triisopropylbiphenyl-2-yl)phosphine-(2'-aminobiphenyl-2-yl)(chloro)palladium (1:1) (3.9 mg, 0.0050 mmol) and potassium phosphate (64 mg, 0.30 mmol) in 1,4-dioxane (1.2 mL)/water (0.2 mL) was degassed with _N2 and then stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, diluted with MeOH, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₅ H ₃₄ N ₉ O ₂ : m/z = 612.3; experimental value: 612.2. ¹ H NMR (600 MHz, DMSO) δ 11.87 (s, 1H), 9.17 (s, 1H), 8.96 (d, J = 4.9 Hz, 2H), 7.97 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.63 (t, J = 7.7 Hz, 2H), 7.59-7.53 (m, 1H), 7.51-7.47 (m, 3H), 7.44 (d, J = 8.6 Hz, 2H), 6.62 (s , 1H), 3.61-3.43 (m, 2H), 3.42-3.32 (m, 1H), 3.16 (q, J = 10.4 Hz, 2H), 2.81 (d, J = 4.5 Hz, 3H), 2.41 (s, 3H), 2.26 (d, J = 14.3 Hz, 2H), 1.93-1.85 (m, 2H). Example 110. N -{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -5- morpholin -4- yl - 2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : N-[4-(4- amino -7- piperidin -4- ylpyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ]-6 -Methyl -5- morpholin - 4- yl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

4-[4-Amino-5-(4-{[(5-bromo-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridin-3-yl)carbonyl ]Amino}phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl]piperidine-1-carboxylic acid tert-butyl ester (52 mg, 0.074 mmol) (from Examples 107, step 5) and a mixture of morpholine (0.10 mL, 1.1 mmol) in DMF (1 mL) was heated under microwave conditions at 180 °C for 60 min, cooled to room temperature, and analyzed via pH 2 preparative LC/MS ( MeCN/water with TFA) was purified and concentrated (removal of Boc occurred during this process) to yield the product as a TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₄ H ₃₇ N ₈ O ₃ : m/z = 605.3; experimental value: 605.4. Step 2 : N-{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ] phenyl }-6- methyl -5- morpholin -4- yl - 2- side oxy -1- phenyl -1,2- dihydropyridine -3- methamide

According to a synthetic sequence similar to Example 107 step 8, use N -[4-(4-amino-7-piperidin-4-ylpyrrolo[2,1- f ][1,2,4]triazine- 5-yl)phenyl]-6-methyl-5-morpholin-4-yl-2-side oxy-1-phenyl-1,2-dihydropyridine-3-methamide instead of N- ( 4-(4-Amino-7-(piperidin-4-yl)pyrrolo[1,2- f ][1,2,4]triazin-5-yl)phenyl)-6-methyl- This compound was prepared from 5-(1-methyl-1 H -pyrazol-4-yl)-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₈ H ₄₃ N ₈ O ₄ : m/z = 675.3; experimental value: 675.3. Example 111. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) Phenyl )-5- cyano -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : ethyl 5- cyano -6- methyl -2- oxy -1- phenyl -1,2- dihydropyridine -3- carboxylate

5-Bromo-6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (300 mg, 0.89 mmol) (from Example 108, step 1), Pd ₂ (dba) ₃ (32.7 mg, 0.036 mmol), Xantphos (41 mg, 0.071 mmol), zinc cyanide (105 mg, 0.89 mmol) and TMEDA (0.040 mL, 0.27 mmol) in DMF (2.5 ml) The mixture was degassed with _N2 and then stirred at 160 °C for 10 min under microwave conditions. After cooling to room temperature, the reaction mixture was filtered through celite (washed with _CH2Cl2 ) and concentrated to give crude product (0.32 g), which was _used directly in the next step. LCMS calculated value (M+H) ⁺ for C ₁₆ H ₁₅ N ₂ O ₃ : m/z = 283.1; experimental value: 283.1. Step 2 : 5- cyano -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

Ethyl 5-cyano-6-methyl-2-oxy-1-phenyl-1,2-dihydropyridine-3-carboxylate (250 mg, 0.89 mmol) and lithium hydroxide monohydrate ( A mixture of 186 mg, 4.43 mmol) in MeOH (7.0 ml)/water (0.70 ml) was stirred at room temperature for 5 h and the MeOH was evaporated. Water was added and the resulting mixture was acidified with IN HCl solution, stirred for another 10 min, filtered and _extracted with _CH2Cl2 . The combined organic layers were dried over _MgSO4 and concentrated to give the product (147 mg, 65%). LCMS calculated value for C ₁₄ H ₁₁ N ₂ O ₃ (M+H) ⁺ : m/z = 255.1; found value: 255.0. Step 3 : 4-(4- amino -5-(4-(5- cyano -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid) Amino ) phenyl ) pyrrolo [2,1-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylic acid tert-butyl ester

To 4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tertiary Butyl ester (200 mg, 0.49 mmol) (from Example 107, step 4), 5-cyano-6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid To a solution of Et3N (124 mg, 0.49 mmol) and _Et3N (0.102 mL, 0.73 mmol) in DMF (4 mL) was added HATU (223 mg, 0.59 mmol). The resulting mixture was stirred at room temperature overnight, water was added and the resulting solid was collected by filtration, washed with water and dried to give a strong yellow solid (307 mg). LCMS calculated value (M+H) ⁺ for C ₃₆ H ₃₇ N ₈ O ₄ : m/z = 645.3; experimental value: 645.4. Step 4 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ) -5- cyano -6- methyl -2- pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide

To 4-(4-amino-5-(4-(5-cyano-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridine-3-methamide) )phenyl)pyrrolo[1,2- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.47 mmol) in CH ₂ Cl ₂ ( To a solution in 4.5 ml) was added 4 M HCl in 1,4-dioxane (0.93 mL, 3.72 mmol). The resulting mixture was stirred at room temperature for 4 h, EtOAc was added and the resulting solid was collected by filtration, washed with EtOAc and dried to give the product as the HCl salt (286 mg). LCMS calculated value (M+H) ⁺ for C ₃₁ H ₂₉ N ₈ O ₂ : m/z = 545.2; experimental value: 545.2. Step 5 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) Phenyl )-5- cyano -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

According to a synthetic sequence similar to Example 107 step 8, use N- (4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1- f ][1,2,4]tri Azin-5-yl)phenyl)-5-cyano-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridine-3-methamide instead of N- (4- (4-Amino-7-(piperidin-4-yl)pyrrolo[1,2- f ][1,2,4]triazin-5-yl)phenyl)-6-methyl-5- This compound was prepared from (1-methyl-1 H -pyrazol-4-yl)-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₅ H ₃₅ N ₈ O ₃ : m/z = 615.3; experimental value: 615.3. Example 111a. N ³ -(4-(4- amino- 7-(1- isobutyrylpiperidin- 4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5- (base ) phenyl )-6- methyl -2- side oxy -1- phenyl -1,2- dihydropyridine -3,5- dimethylamide

The synthesis sequence described in Example 111 yields this compound as a by-product due to hydrolysis of the cyano group. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated value (M+H) ⁺ for C ₃₅ H ₃₇ N ₈ O ₄ : m/z = 633.3; experimental value: 633.3. Example 112. 5- acetyl - N- (4-(4- amino -7-(1- isobutyrylpiperidin- 4- yl ) pyrrolo [1,2- f ][1,2,4] Triazin -5- yl ) phenyl )-6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 5- acetyl -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid ethyl ester

5-Bromo-6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (0.46 g, 1.37 mmol) (from Example 108, step 1), A mixture of palladium(II) acetate (7.7 mg, 0.034 mmol) in 1-butyl-3-methylimidazolium tetrafluoroborate (2.81 mL, 15.1 mmol) was evacuated and backfilled with N _three times. To this mixture 1-(ethyleneoxy)butane (0.90 mL, 6.84 mmol) and _Et3N (0.23 mL, 1.64 mmol) were added and the reaction mixture was stirred at 115°C overnight. The resulting mixture was then cooled to room temperature, treated with HCl solution (7.07 ml, 11.63 mmol), stirred at room temperature for 30 min and _extracted with _CH2Cl2 . The combined organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexane) to give the product (0.22 g, 54%). LCMS calculated for C ₁₇ H ₁₈ NO ₄ (M+H) ⁺ : m/z = 300.1. Experimental value: 300.2. Step 2 : 5- acetyl -6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

5-Acetyl-6-methyl-2-side-oxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (0.070 g, 0.23 mmol) was dissolved in 1 M NaOH solution (1.0 mL) and MeOH (2.0 mL) was stirred at room temperature for 1 h and then neutralized to pH ~5 with 1 N HCl solution. The resulting solid was collected by filtration and dried to yield product (0.052 g, 82%). LCMS calculated for C ₁₅ H ₁₄ NO ₄ (M+H) ⁺ : m/z = 272.1. Experimental value: 272.1. Step 3 : 5- acetyl -N-(4-(4- amino -7-(1- isobutyrylpiperidin- 4- yl ) pyrrolo [1,2-f][1,2,4] Triazin -5- yl ) phenyl )-6- methyl -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

According to a synthetic sequence similar to Example 83 step 5, using 5-acetyl-6-methyl-2-sideoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid instead of 1-isopropyl This compound was prepared using 2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₆ H ₃₈ N ₇ O ₄ (M+H) ⁺ : m/z = 632.3. Experimental value: 632.4. ¹ H NMR (500 MHz, DMSO) δ 11.67 (s, 1H), 8.95 (s, 1H), 8.00 (s, 1H), 7.86-7.78 (m, 2H), 7.66-7.59 (m, 2H), 7.59 -7.53 (m, 1H), 7.50-7.37 (m, 4H), 6.67 (s, 1H), 4.57-4.51 (m, 1H), 4.09-4.01 (m, 1H), 3.47-3.36 (m, 1H) , 3.27-3.15 (m, 1H), 2.97-2.83 (m, 1H), 2.73-2.66 (m, 1H), 2.63 (s, 3H), 2.31 (s, 3H), 2.09-1.96 (m, 2H) , 1.68-1.45 (m, 2H), 1.01 (t, J = 6.8 Hz, 6H). Example 113. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) Phenyl )-1-(5- fluoropyridin -3- yl )-2,5- bisoxy - 1,2,5,6,7,8 -hexahydroquinoline -3- methamide Step 1 : Ethyl 2,5- bisoxy -5,6,7,8- tetrahydro -2H- chromene -3- carboxylate

To a mixture of cyclohexane-1,3-dione (1.0 g, 8.9 mmol) in DMF (10 mL) was added 1 M t -BuOK in THF (8.9 mL, 8.9 mmol) at 0°C. The resulting mixture was stirred for 20 min and ( E )-ethyl 2-cyano-3-ethoxyacrylate (1.51 g, 8.9 mmol) was added. The reaction mixture was warmed to room temperature, stirred for 2 h, quenched with 1N HCl solution and extracted with EtOAc. The combined organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexanes) to yield the product. LCMS calculated for C ₁₂ H ₁₃ O ₅ (M+H) ⁺ : m/z = 237.1. Experimental value: 237.2. Step 2 : 1-(5- fluoropyridin -3- yl )-2,5- bisoxy -1,2,5,6,7,8 -hexahydroquinoline -3- carboxylic acid

2,5-Bipoxy-5,6,7,8-tetrahydro- 2H -chromene-3-carboxylic acid ethyl ester (0.28 g, 1.185 mmol) and 5-fluoropyridin-3-amine (0.133 g, 1.19 mmol) in EtOH (3 mL) was stirred at room temperature overnight, treated with 1 M NaOH solution (2 mL), stirred at room temperature for 1 h and analyzed by pH 2 preparative LC/MS (MeCN /water with TFA) to yield product (0.065 g, 18%). LCMS calculated for C ₁₅ H ₁₂ FN ₂ O ₄ (M+H) ⁺ : m/z = 303.1. Experimental value: 303.2. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-1-(5- fluoropyridin -3- yl )-2,5- bisoxy - 1,2,5,6,7,8 -hexahydroquinoline -3- methamide

According to the synthesis sequence similar to step 5 of Example 83, use 1-(5-fluoropyridin-3-yl)-2,5-bisoxy-1,2,5,6,7,8-hexahydroquinoline This compound was prepared by replacing 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid with -3-carboxylic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₆ H ₃₆ FN ₈ O ₄ (M+H) ⁺ : m/z = 663.3. Experimental value: 663.4. ¹ H NMR (600 MHz, DMSO) δ 11.38 (s, 1H), 8.96 (s, 1H), 8.86 (d, J = 2.6 Hz, 1H), 8.68-8.62 (m, 1H), 8.16-8.12 (m , 1H), 8.09 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.58-4.51 (m, 1H) , 4.12-4.03 (m, 1H), 3.46-3.36 (m, 1H), 3.26-3.16 (m, 1H), 2.94-2.85 (m, 1H), 2.75-2.63 (m, 1H), 2.63-2.52 ( m, 4H), 2.09-1.95 (m, 4H), 1.69-1.47 (m, 2H), 1.06-0.93 (m, 6H). Example 114. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-7,7- dimethyl -2,5- bisoxy -1-( pyridin -3- yl )-1,2,5,6,7,8 -hexahydroquinoline -3 -Formamide _ Step 1 : 7,7- dimethyl -2,5- bisoxy- 5,6,7,8- tetrahydro -2H- chromene - 3- carboxylic acid ethyl ester

To a mixture of 5,5-dimethylcyclohexane-1,3-dione (2.0 g, 14.3 mmol) in DMF (20 mL) was added 1 M t -BuOK in THF (14.3 mL) at 0 °C. ,14.3 mmol). The resulting mixture was stirred for 20 min, ( E )-ethyl 2-cyano-3-ethoxyacrylate (2.41 g, 14.3 mmol) was added, warmed to room temperature and stirred overnight. The reaction mixture was quenched with 1 N HCl solution, extracted with EtOAc and the combined organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexane) to yield the product (2.8 g, 74%). LCMS calculated for C ₁₄ H ₁₇ O ₅ (M+H) ⁺ : m/z = 265.1. Experimental value: 265.2. Step 2 : 7,7- dimethyl -2,5- bisoxy -1-( pyridin -3- yl )-1,2,5,6,7,8- hexahydroquinoline -3- carboxylic acid

Ethyl 7,7-dimethyl-2,5-bisoxy-5,6,7,8-tetrahydro- 2H -chromene-3-carboxylate (244 mg, 0.92 mmol) and pyridine- A mixture of 3-amine (87 mg, 0.92 mmol) in EtOH (3 mL) was stirred at 60 °C overnight, cooled to room temperature and the resulting solid was collected by filtration and dried to give the product (170 mg, 59%). LCMS calculated for C ₁₇ H ₁₇ N ₂ O ₄ (M+H) ⁺ : m/z = 313.1. Experimental value: 313.2. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-7,7- dimethyl -2,5- bisoxy -1-( pyridin -3- yl )-1,2,5,6,7,8 -hexahydroquinoline -3 -Formamide _

According to the synthesis sequence similar to step 5 of Example 83, use 7,7-dimethyl-2,5-bisoxy-1-(pyridin-3-yl)-1,2,5,6,7,8 - Hexahydroquinoline-3-carboxylic acid instead of 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid to prepare this compound. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₈ H ₄₁ N ₈ O ₄ (M+H) ⁺ : m/z = 673.3. Experimental value: 673.4. ¹ H NMR (500 MHz, DMSO) δ 11.44 (s, 1H), 8.95 (s, 1H), 8.80 (dd, J = 4.8, 1.4 Hz, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.09 (s, 1H), 8.01 (dt, J = 8.1, 1.9 Hz, 1H), 7.84 (d, J = 8.6 Hz, 2H), 7.73 (dd, J = 8.1, 4.8 Hz, 1H), 7.47 (d , J = 8.6 Hz, 2H), 6.76 (s, 1H), 4.59-4.49 (m, 1H), 4.12-4.03 (m, 1H), 3.46-3.37 (m, 1H), 3.26-3.15 (m, 1H ), 2.96-2.84 (m, 1H), 2.74-2.65 (m, 1H), 2.49-2.42 (m, 4H), 2.11-1.96 (m, 2H), 1.69-1.46 (m, 2H), 1.10-0.89 (m, 12H). Example 115. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1-(5- fluoropyridin -3- yl )-6,6- dimethyl -2,5 -bisoxy -1,2,5,6,7,8- hexahydroquin Phylline -3- methamide Step 1 : 6,6- dimethyl -2,5- bisoxy -5,6,7,8- tetrahydro -2H- chromene - 3- carboxylic acid ethyl ester

To a mixture of 4,4-dimethylcyclohexane-1,3-dione (1.8 g, 12.8 mmol) in DMF (10 mL) at 0 °C was added 1 M t -BuOK (12.8 mL, 12.8 mmol). The resulting mixture was stirred for 20 min, ( E )-ethyl 2-cyano-3-ethoxyacrylate (2.17 g, 12.8 mmol) was added, warmed to room temperature and stirred overnight. The reaction mixture was quenched with 1 N HCl solution, extracted with EtOAc and the combined organic layers were concentrated and purified via column chromatography (0% to 100% EtOAc in hexane) to yield the product (2.7 g, 80%). LCMS calculated for C ₁₄ H ₁₇ O ₅ (M+H) ⁺ : m/z = 265.1. Experimental value: 265.2. Step 2 : 1-(5- fluoropyridin -3- yl )-6,6- dimethyl -2,5 -bisoxy -1,2,5,6,7,8 - hexahydroquinoline- 3- Formic acid

6,6-Dimethyl-2,5-bisoxy-5,6,7,8-tetrahydro- 2H -chromene-3-carboxylic acid ethyl ester (200 mg, 0.76 mmol) and 5- A mixture of fluoropyridin-3-amine (85 mg, 0.76 mmol) in EtOH (3 mL) was stirred at 60 °C overnight, cooled to room temperature and subjected to pH 2 preparative LC/MS (MeCN/water with TFA) Purification yielded product (75 mg, 30%). LCMS calculated for C ₁₇ H ₁₆ FN ₂ O ₄ (M+H) ⁺ : m/z = 331.1. Experimental value: 331.2. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-1-(5- fluoropyridin -3- yl )-6,6- dimethyl -2,5 -bisoxy -1,2,5,6,7,8- hexahydroquin Phylline -3- methamide

According to a synthetic sequence similar to step 5 of Example 83, using 1-(5-fluoropyridin-3-yl)-6,6-dimethyl-2,5-dilateral oxy-1,2,5,6, 7,8-hexahydroquinoline-3-carboxylic acid instead of 1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine- 5-Formic acid was used to prepare this compound. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₈ H ₄₀ FN ₈ O ₄ (M+H) ⁺ : m/z = 691.3. Experimental value: 691.4. Example 116. N -{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ] phenyl }-6- side oxy -1- phenyl -2- pyridin -3- yl -1,6- dihydropyrimidine -5- methamide Step 1 : [ Imino ( pyridin -3- yl ) methyl ]( phenyl ) sodium cyanate

Aniline (931 mg, 10.0 mmol) was added to 1.0 M sodium hexamethyldisilazine (10 mL, 10.0 mmol) in THF. The resulting mixture was stirred at room temperature for 10 min, 3-pyridinecarbonitrile (1.04 g, 10.0 mmol) was added, stirred at room temperature for 1 h and concentrated. The residue was treated with diethyl ether and the resulting solid was collected by filtration, washed with diethyl ether and dried to give the product (2.10 g, 100%) which was used directly in the next step. LCMS calculated for C ₁₂ H ₁₂ N ₃ (M+2H-Na) ⁺ : m/z = 198.1. Experimental value: 198.1. Step 2 : 6- Pendant oxy -1- phenyl -2- pyridin -3- yl -1,6- dihydropyrimidine -5- carboxylate ethyl ester

To a solution of sodium [imino(pyridin-3-yl)methyl](phenyl)cyanate (0.219 g, 1.00 mmol) in MeCN (5 mL) was added ammonium chloride (0.054 g, 1.00 mmol) , then diethyl (ethoxymethylene)malonate (0.20 mL, 1.00 mmol) was added. The reaction mixture was stirred at 80 °C for 2 h, cooled to room temperature and concentrated. The residue obtained was dissolved in EtOAc and washed with water and brine. The organic layer was separated, dried over MgSO4, concentrated and purified via column chromatography (0% to 50% EtOAc in hexane) to yield the product (0.167 g, 52%). LCMS calculated for C ₁₈ H ₁₆ N ₃ O ₃ (M+H) ⁺ : m/z = 322.1. Experimental value: 322.2. Step 3 : 6- Pendant oxy -1- phenyl -2- pyridin -3- yl -1,6- dihydropyrimidine -5- carboxylic acid

6-Penyloxy-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylic acid ethyl ester (133 mg, 0.41 mmol) and lithium iodide (138 mg, 1.03 mmol ) in pyridine (2.5 mL) was stirred at 115°C overnight, cooled to room temperature and concentrated. The resulting residue was dissolved in water (2 mL) and extracted with EtOAc (3 mL×2). The aqueous layer was slowly acidified with 1 N HCl solution to pH approximately 4 and extracted with 5% MeOH in CH ₂ Cl ₂ (3 mL × 3). The combined organic layers were washed with brine, dried over _MgSO4 and concentrated to give product (0.103 g, 85%) which was used directly in the next step. LCMS calculated for C ₁₆ H ₁₂ N ₃ O ₃ (M+H) ⁺ : m/z = 294.1. Experimental value: 294.1. Step 4 : N-{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ] phenyl }-6- side oxy -1- phenyl -2- pyridin -3- yl -1,6- dihydropyrimidine -5- methamide

According to the synthetic sequence similar to Example 83 step 5, using 6-side oxy-1-phenyl-2-pyridin-3-yl-1,6-dihydropyrimidine-5-carboxylic acid instead of 1-isopropyl-2 ,4-bis-oxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid to prepare this compound. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₇ H ₃₆ N ₉ O ₃ (M+H) ⁺ : m/z = 654.3. Experimental value: 654.3. Example 117. N -{4-[4- Amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ] phenyl }-6- cyclopropyl -3- side oxy -2- phenyl -2,3- dihydropyrazine -4- methamide Step 1. (2- Cyclopropyl -2- Pendantoxyethyl )( triphenyl ) phosphonium bromide

A solution of 2-bromo-1-cyclopropylethanone (2.44 g, 15.0 mmol) and PPh ₃ (3.93 g, 15.0 mmol) in THF (60 mL) was stirred at reflux for 1 h and cooled to room temperature. The resulting solid was collected by filtration and washed with diethyl ether to yield product (3.91 g, 61%), which was used directly in the next step. LCMS calculated for C ₂₃ H ₂₂ OP (M-Br) ⁺ : m/z = 345.1. Experimental value: 345.2. Step 2 : 1- Cyclopropyl -2-( triphenylphosphinylene ) ethanone

A mixture of (2-cyclopropyl-2-pentoxyethyl)(triphenyl)phosphonium bromide (3.91 g, from the previous step) in 1 N NaOH solution (40 mL) was stirred overnight and treated with CH ₂ Cl ₂ extraction. The combined organic layers were washed with brine, dried over _MgSO4 and concentrated to give the product (2.60 g, 50%). LCMS calculated value for C ₂₃ H ₂₂ OP (M+H) ⁺ : m/z = 345.1. Experimental value: 345.2. Step 3 : 6- Cyclopropyl -3- Pendantoxy -2- phenyl -2,3- dihydropyrazine -4- carboxylic acid

To a solution of 1-cyclopropyl-2-(triphenylphosphinylene)ethanone (1.72 g, 5.0 mmol) in THF (25 mL) was added diethyl 2-pendantoxymalonate (1.3 g, 7.5 mmol). The resulting mixture was stirred at room temperature for 30 min, concentrated and the residue was added to phenylhydrazine hydrochloride (1.08 g, 7.50 mmol) in EtOH/ _H2O (1:1, 50 mL). The reaction mixture was stirred at 80°C overnight. After cooling to room temperature, _the organic solvent was evaporated and the residue was diluted with _CH2Cl2 (30 mL) and extracted with IN NaOH solution (5 mL×3). The combined aqueous layers were adjusted to pH approximately 4 with 6 N HCl and extracted with EtOAc (5 mL×3). The combined organic layers were washed with water and brine, dried over _MgSO4 and concentrated to give the product (0.562 g, 44%) which was used directly in the next step. LCMS calculated for C ₁₄ H ₁₃ N ₂ O ₃ (M+H) ⁺ : m/z = 257.1. Experimental value: 257.1. Step 4 : N-{4-[4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ] phenyl }-6- cyclopropyl -3- side oxy -2- phenyl -2,3- dihydropyrazine -4- methamide

According to the synthetic sequence similar to step 5 of Example 83, using 6-cyclopropyl-3-side oxy-2-phenyl-2,3-dihydropyrazine-4-carboxylic acid instead of 1-isopropyl-2, This compound was prepared by 4-bis-oxy-3-(pyridin-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₅ H ₃₇ N ₈ O ₃ (M+H) ⁺ : m/z = 617.3. Experimental value: 617.3. Example 118. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -6- methyl - 2- sideoxy - 2H- [1,2'- bipyridyl ]-3- methamide Step 1 : 5- bromo -6- methyl -2- sideoxy -2H-[1,2'- bipyridine ]-3- carboxylic acid

5-Bromo-6-methyl-2-pendantoxy- 2H- [1,2'-bipyridine]-3-carboxylic acid was treated with lithium hydroxide monohydrate (0.33 mL, 11.9 mmol) at 0 °C. A mixture of ethyl ester (800 mg, 2.37 mmol) (from Affinity Research Chemicals) in THF (7.9 mL)/MeOH (5.3 mL)/water (2.6 mL). The reaction mixture was stirred at room temperature for 60 min, concentrated and water was added. The resulting mixture was neutralized to pH 6~7 with 12 M HCl solution and the resulting solid was collected by filtration, washed with water and dried to yield the product as a light yellow powder (784 mg, 100%). LCMS calculated for C ₁₂ H ₁₀ BrN ₂ O ₃ (M+H) ⁺ : m/z = 309.0. Experimental value: 309.0. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -6- methyl -2- sideoxy -2H-[1,2'- bipyridyl ]-3- methamide

To 5-bromo-6-methyl-2-pendantoxy- 2H- [1,2'-bipyridyl]-3-carboxylic acid (9.0 mg, 0.03 mmol) and 1-(4-(4-amino -5-(4-Aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidin-1-yl)-2-methylpropan-1- To a mixture of ketone (10 mg, 0.03 mmol) (from Example 83, step 2) in DMF (528 µl) was added _Et3N (11 µl, 0.08 mmol), followed by HATU (20 mg, 0.053 mmol). The resulting mixture was stirred at room temperature for 20 min, filtered and the crude material was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₃ H ₃₄ BrN ₈ O ₃ (M+H) ⁺ : m/z = 669.2. Experimental value: 669.2. ¹ H NMR (500 MHz, DMSO) δ 11.69 (s, 1H), 8.75-8.67 (m, 2H), 8.60 (s, 1H), 8.17 (td, J = 7.8, 1.9 Hz, 1H), 8.05 (s , 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.73-7.62 (m, 3H), 7.46 (d, J = 8.6 Hz, 1H), 6.72 (s, 1H), 4.55 (d, J = 13.6 Hz, 1H), 4.07 (d, J = 12.2 Hz, 1H), 3.42 (s, 1H), 3.27-3.16 (m, 1H), 2.91 (p, J = 6.7 Hz, 1H), 2.78-2.61 ( m, 2H), 2.16 (s, 2H), 2.12-1.95 (m, 2H), 1.58 (dd, J = 59.5, 11.1 Hz, 2H), 1.02 (t, J = 6.6 Hz, 6H). Example 119. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -6- methyl -5-( oxazol -2- yl )-4- side oxy -1,4- dihydropyridine -3- carboxamide Step 1 : 1- Cyclopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

Feed ( E/Z )-3-((dimethylamino)methylene)-6-methyl- 2H -piran-2,4( 3H )-dione (1.92 g) into the microwave vial. , 7.95 mmol) (from Example 97, Step 1), cyclopropylamine (0.83 mL, 11.92 mmol) and t -BuONa (1.13 g, 11.76 mmol) in EtOH (5.0 mL). The resulting mixture was stirred at 90 °C for 18 h, cooled to room temperature, concentrated and _partitioned between water and _CH2Cl2 . The aqueous layer was acidified with 4 N HCl solution and _extracted with _CH2Cl2 . The combined organic layers were washed with water, _brine , dried over _Na2SO4 and concentrated to give the product (1.1 g, 42%). LCMS calculated for C ₁₀ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 194.1. Experimental value: 194.1. Step 2 : 5- Bromo -1- cyclopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

1-Cyclopropyl-6-methyl-4-pendantoxy-1,4-dihydropyridine-3-carboxylic acid (0.83 g, 4.30 mmol) was treated with Br ₂ (0.29 mL, 5.58 mmol) in glacial acetic acid ( 6.0 mL) and the reaction mixture was stirred at room temperature for 4 days. Additional _Br2 (100 μL) was added and the reaction mixture was stirred overnight, diluted with water and the resulting solid collected by filtration, washed with water and dried to give the product as a beige solid (1.0 g, 86%). LCMS calculated for C ₁₀ H ₁₁ BrNO ₃ (M+H) ⁺ : m/z = 272.0. Experimental value: 272.0. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -1- cyclopropyl -6- methyl - 4- sideoxy -1,4- dihydropyridine -3- methamide

1-(4-(4-Amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (278 mg, 0.74 mmol) (from Example 83, Step 2), 5-bromo-1-cyclopropyl-6-methyl-4-pendantoxy-1 , a mixture of 4-dihydropyridine-3-carboxylic acid (200 mg, 0.74 mmol), HATU (335 mg, 0.88 mmol) and Et ₃ N (0.21 mL, 1.47 mmol) in DMF (5.0 mL) at room temperature. Stirred for 2 h and then directly purified via column chromatography to yield product (252 mg, 54%). LCMS calculated for C ₃₁ H ₃₅ BrN ₇ O ₃ (M+H) ⁺ : m/z = 632.2. Experimental value: 632.1. Step 4 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -6- methyl -5-( oxazol -2- yl )-4- side oxy -1,4- dihydropyridine -3- carboxamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (20 mg, 0.032 mmol) and 2-(tributyltin To a solution of alkyl)oxazole (11 mg, 0.032 mmol) in 1,4-dioxane (2.0 mL) was added Pd(Ph ₃ P) ₄ (7.3 mg, 6.3 µmol). The reaction mixture was stirred at reflux overnight, cooled to room temperature and the resulting mixture was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₄ H ₃₇ N ₈ O ₄ (M+H) ⁺ : m/z = 621.3. Experimental value: 621.3. Example 120. ( S )- N -(4-(4- amino- 7-(1- isobutyrylpiperidin- 4- yl ) pyrrolo [2,1- f ][1,2,4] triazine -5- yl ) phenyl )-5-(3- hydroxybut-1-yn- 1 - yl )-2- side oxy - 1- phenyl - 1,2- dihydropyridine -3- methamide Step 1 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

1-(4-(4-Amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (257 mg, 0.68 mmol) (from Example 83, Step 2), 5-bromo-2-pentanoxy-1-phenyl-1,2-dihydropyridine A mixture of -3-carboxylic acid (200 mg, 0.68 mmol), HATU (310 mg, 0.82 mmol) and Et ₃ N (0.19 mL, 1.36 mmol) in DMF (5.0 mL) was stirred at room temperature for 2 h. The reaction mixture was subsequently purified via column chromatography to yield product (310 mg, 70%). LCMS calculated for C ₃₃ H ₃₃ BrN ₇ O ₃ (M+H) ⁺ : m/z = 654.2. Experimental value: 654.3. Step 2 : (S)-N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazine -5- yl ) phenyl )-5-(3- hydroxybut-1-yn- 1 - yl )-2- side oxy - 1- phenyl - 1,2- dihydropyridine -3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (20 mg, 0.031 mmol) was dissolved in MeCN (10 mL), and ( S )-but-3-yn-2-ol (4.7 mg, 0.067 mmol), tris(tert-butyl)phosphine (1.0 mL), Pd(Ph ₃ P) ₄ (3.5 mg, 3.1 µmol), iodide Copper(I) (0.36 mg, 1.9 µmol) and Et ₃ N (0.019 mL, 0.14 mmol). The resulting mixture was stirred at 70°C for 16 h, cooled to room temperature and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₇ H ₃₈ N ₇ O ₄ (M+H) ⁺ : m/z = 644.3. Experimental value: 644.5. Example 121. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5'- fluoro -5,6- dimethyl -2- sideoxy - 2H- [1,3'- bipyridyl ]-3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene methyl)-5-bromo-5'-fluoro-6-methyl-2-pendantoxy- 2H- [1,3'-bipyridyl]-3-methamide (8.0 mg, 0.012 mmol) (Example 101, step 2) and a mixture of PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (1.0 mg, 1.2 µmol) in 1,4-dioxane (0.50 mL) was sealed in a microwave vial, evacuated and The _N was refilled several times, followed by the addition of 2.0 M dimethylzinc in toluene (0.023 mL, 0.047 mmol). The reaction mixture was heated and stirred at 90 °C for 1 h, cooled to room temperature and quenched with ice water. The crude material was diluted with DMF and purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to give the desired product as a white solid. LCMS calculated for C ₃₄ H ₃₆ FN ₈ O ₃ (M+H) ⁺ : m/z = 623.3. Experimental value: 623.3. Example 122. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-5-( cyanomethyl )-6- methyl -2- sideoxy -1-( pyridin -2- yl )-1,2- dihydropyridine -3- carboxamide

In a sealed tube, add N- (4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine -5-yl)phenyl)-5-bromo-6-methyl-2-sideoxy- 2H- [1,2'-bipyridyl]-3-methamide (10 mg, 0.02 mmol)( Example 118, step 2), isoxazol-4-ylboronic acid (2.5 mg, 0.02 mmol) in 1,4-dioxane (0.30 mL), N -ethyl- N -isopropylpropan-2-amine (7.7 µL, 0.05 mmol) and water (60 µL) were stirred together before adding Pd( t Bu ₃ ) ₂ (3.8 mg, 7.5 µmol). The reaction mixture was sealed and then heated and stirred at 110 °C for 1 h, cooled to room temperature, diluted with DMF and purified via pH 10 preparative LC/MS (MeCN/water with NH ₄ OH) to yield as a white solid desired product. LCMS calculated for C ₃₅ H ₃₆ N ₉ O ₃ (M+H) ⁺ : m/z = 630.3. Experimental value: 630.3. Example 123. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-(1- methyl - 1H - pyrazol -5- yl )-2- sideoxy - 2H- [1,2'- bipyridyl ]-3- Formamide

In a sealed tube, add N- (4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine -5-yl)phenyl)-5-bromo-6-methyl-2-sideoxy- 2H- [1,2'-bipyridyl]-3-methamide (8.0 mg, 0.012 mmol)( Example 118, step 2), (1-methyl-1 H -pyrazol-5-yl)boronic acid (2.3 mg, 0.02 mmol) and DIPEA (4.6 mg, 0.036 mmol) in 1,4-dioxane (200 µL) and water (40 µL) were stirred together before adding Pd( t Bu ₃ ) ₂ (3.1 mg, 6 µmol). The reaction mixture was sealed and then heated and stirred at 110°C for 50 min, cooled to room temperature, diluted with DMF and purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to give desired product. LCMS calculated for C ₃₇ H ₃₉ N ₁₀ O ₃ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.3. ¹ H NMR (500 MHz, DMSO) δ 11.74 (s, 1H), 8.74 (dd, J = 4.9, 1.1 Hz, 1H), 8.38 (s, 1H), 8.18 (td, J = 7.8, 1.9 Hz, 1H ), 7.91 (s, 1H), 7.80 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.70-7.63 (m, 1H), 7.56 (d, J = 1.8 Hz , 1H), 7.43 (d, J = 8.6 Hz, 2H), 6.58 (s, 1H), 6.42 (d, J = 1.9 Hz, 1H), 4.54 (d, J = 11.9 Hz, 1H), 3.74 (s , 3H), 3.61 (s, 1H), 3.40 (t, J = 11.9 Hz, 1H), 3.25-3.12 (m, 1H), 2.91 (p, J = 6.8 Hz, 1H), 2.75-2.60 (m, 1H), 2.16-1.97 (m, 1H), 1.87 (s, 3H), 1.81-1.73 (m, 1H), 1.51 (d, J = 13.9 Hz, 2H), 1.02 (t, J = 6.6 Hz, 6H ). Example 124. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) Phenyl )-5- chloro -6- methyl -2- sideoxy - 2H- [1,2'- bipyridyl ]-3- methamide

To a microwave vial, add N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine- 5-yl)phenyl)-5-bromo-6-methyl-2-sideoxy- 2H- [1,2'-bipyridyl]-3-methamide (8.0 mg, 0.01 mmol) (Example 118, step 2) and nickel(II) chloride (1.4 mg, 0.02 mmol) in DMF (0.40 mL). The vial was sealed and the reaction mixture was stirred under microwave conditions at 180°C for 30 min, cooled to room temperature and purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to yield a white solid. Need products. LCMS calculated for C ₃₃ H ₃₄ ClN ₈ O ₃ (M+H) ⁺ : m/z = 625.2. Experimental value: 625.2. Example 125. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-(1- methyl - 1H - pyrazol -3- yl )-2- side oxy - 2H- [1,2'- bipyridyl ]-3- Formamide

According to a synthetic sequence similar to Example 123, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H - was used This compound was prepared by substituting pyrazole for (1-methyl-1 H -pyrazol-5-yl)boronic acid. This compound was purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to give the desired product as a white solid. LCMS calculated for C ₃₇ H ₃₉ N ₁₀ O ₃ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.3. Example 126. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-( oxazol -2- yl )-2- pendantoxy - 2H- [1,2'- bipyridyl ]-3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (1,2'- bipyridyl ]-3-methamide (10 mg, 0.02 mmol) (Example 118, Step 2) To a mixture of Pd(Ph ₃ P) ₄ (3.5 mg, 3.0 µmol) in toluene (0.30 mL) was added 2-(tributylstannyl)oxazole (10.7 mg, 0.03 mmol). The reaction mixture was sealed in a microwave vial, evacuated and backfilled with _N2 several times, and then heated and stirred at 120 °C for 22 h. The reaction mixture was cooled to room temperature, concentrated and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₆ H ₃₆ N ₉ O ₄ (M+H) ⁺ : m/z = 658.3. Experimental value: 658.3. Example 127. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5-( difluoromethyl )-6- methyl -2- sideoxy - 2H- [1,2'- bipyridyl ]-3- methamide Step 1 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -2- sideoxy -5- vinyl -2H-[1,2'- bipyridyl ]-3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (40 mg , 0.06 mmol) (Example 118, step 2) , 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaboropentane (13.8 mg, 0.09 mmol), Na ₂ CO ₃ (20.9 mg, 0.20 mmol) and [ A mixture of 1,1′-bis(di-cyclohexylphosphino)ferrocene]dichloropalladium(II) (4.5 mg, 6.0 µmol) in tert-butanol (0.19 mL) and water (0.07 mL). Degassed with nitrogen and then stirred and heated at 115 °C for 2 h. The resulting mixture was cooled to room temperature, diluted with EtOAc, washed with saturated _NaHCO3 solution, water and _brine , dried over _Na2SO4 , concentrated and purified via column chromatography (0 to 15% MeOH in EtOAc) to yield The desired product was obtained as a creamy white solid (27.9 mg, 76%). LCMS calculated for C ₃₅ H ₃₇ N ₈ O ₃ (M+H) ⁺ : m/z = 617.3. Experimental value: 617.3. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-5- formamide -6- methyl -2- sideoxy -2H-[1,2'- bipyridyl ]-3- formamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (20.0 mg , 0.032 mmol) in THF (0.37 mL) OsO ₄ (4 wt.%) in water (0.06 mL, 9.7 µmol) and sodium periodate (32.6 mg, 0.15 mmol) in water (0.03 mL) were added to the solution. The reaction mixture was stirred at 70 °C for 1 h, cooled to room temperature, filtered through a plug of celite, rinsed with THF, concentrated and purified via pH 10 preparative LC/MS (MeCN/water with _NH4OH ) to The desired product was produced as a pale yellow solid (6.5 mg, 31%). LCMS calculated for C ₃₄ H ₃₅ N ₈ O ₄ (M+H) ⁺ : m/z = 619.3. Experimental value: 619.3. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-5-( difluoromethyl )-6- methyl -2- sideoxy -2H-[1,2'- bipyridyl ]-3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine-5 at 0°C -(yl)phenyl)-5-formamide-6-methyl-2-sideoxy- 2H- [1,2'-bipyridyl]-3-formamide (8.0 mg, 0.01 mmol) in To a solution in THF (0.16 mL) was slowly added (diethylamino)sulfur trifluoride (DAST) (0.034 mL, 0.259 mmol). The resulting reaction mixture was warmed to and stirred at room temperature for 21 h, diluted with DMF, and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated value for C ₃₄ H ₃₅ F ₂ N ₈ O ₃ (M+H) ⁺ : m/z =641.3. Experimental value: 641.3. Example 128. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -4- pendantoxy -5-( pyridin -3- yl )-1,4- dihydropyridine -3- methamide Step 1 : Methyl 5- bromo -1- isopropyl -4- oxy -1,4- dihydropyridine -3- carboxylate

Dissolve 5-bromo-4-pentoxy-1,4-dihydropyridine-3-carboxylic acid methyl ester (151 mg, 0.65 mmol) and Cs ₂ CO ₃ (420 mg, 1.3 mmol) in DMF (3 mL) The mixture was stirred at room temperature for 15 min and then 2-iodopropane (0.16 mL, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 11 days, diluted with EtOAc, filtered through celite, concentrated and subjected to column chromatography (0% to 100% EtOAc in hexane followed by 0% to 10 _% in _CH2Cl2 % methanol) to yield the product as a milky white solid (103 mg, 58%). LCMS calculated for C ₁₀ H ₁₃ BrNO ₃ (M+H) ⁺ : m/z = 274.0. Experimental value: 274.1. Step 2 : 5- bromo -1- isopropyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

To a solution of 5-bromo-1-isopropyl-4-pendantoxy-1,4-dihydropyridine-3-carboxylic acid methyl ester (103 mg, 0.376 mmol) in MeOH (2 mL) was added 3 M NaOH (0.2 mL) and the reaction mixture was stirred at room temperature for 4 h, acidified with 1 N HCl, diluted with brine and extracted with EtOAc. The combined organic layers were dried over _Na2SO4 and concentrated to yield the crude product as _a cream solid, which was used directly in the next step (97 mg, 99%). LCMS calculated for C ₉ H ₁₁ BrNO ₃ (M+H) ⁺ : m/z = 260.0. Experimental value: 260.0. Step 3 : 4-(4- amino- 5-(4-(5- bromo -1- isopropyl -4- sideoxy -1,4- dihydropyridine - 3-methamide ) phenyl ) pyrrolo [1,2-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylic acid tert-butyl ester

5-Bromo-1-isopropyl-4-sideoxy-1,4-dihydropyridine-3-carboxylic acid (83 mg, 0.319 mmol) and HATU (146 mg, 0.383 mmol) in DMF (2 mL). This mixture was then added via cannula to 4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2- f ][1,2,4]triazin-7-yl) A solution of piperidine-1-carboxylic acid tert-butyl ester (130 mg, 0.319 mmol) (Example 107, Step 4) in DMF (1 mL). The reaction mixture was stirred at room temperature for 40 min, diluted with water and extracted twice with EtOAc. The combined organic layers were washed with _brine , dried over _Na2SO4 , concentrated and subjected to column chromatography (0% to 100% EtOAc in _hexanes , followed by 0% to 10% MeOH in _CH2Cl2 ) Purification gave the product as a yellow solid (208 mg, 100%). LCMS calculated for C ₃₁ H ₃₇ BrN ₇ O ₄ (M+H) ⁺ : m/z = 650.2. Experimental value: 650.2. Step 4 : 4-(4- amino -5-(4-(1- isopropyl -4- sideoxy -5-( pyridin -3- yl )-1,4- dihydropyridine -3- methyl tert-Butyl amide ) phenyl ) pyrrolo [1,2-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylate

4-(4-Amino-5-(4-(5-bromo-1-isopropyl-4-sideoxy-1,4-dihydropyridine-3-methamide)phenyl)pyrrole And[1,2- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (76 mg, 0.117 mmol), pyridin-3-ylboronic acid (17.2 mg, A mixture of XPhos-Pd-G2 (9.2 mg, 0.012 mmol) and tripotassium phosphate (62 mg, 0.292 mmol) in 1,4-dioxane/water (5:1, 2.4 mL) was added with nitrogen Degas and then heat and stir at 90 °C for 2 h. The reaction mixture was cooled _to room temperature, diluted with EtOAc, dried over _Na2SO4 , filtered through _celite , concentrated and subjected to column chromatography (0% to 100% EtOAc in hexane followed by _CH2Cl2 0% to 10% MeOH) to yield the product as a creamy white solid (60 mg, 79%). LCMS calculated for C ₃₆ H ₄₁ N ₈ O ₄ (M+H) ⁺ : m/z = 649.3. Experimental value: 649.3. Step 5 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin -5- yl ) phenyl ) -1- Isopropyl -4- Pendantoxy -5-( pyridin -3- yl )-1,4- dihydropyridine -3- carboxamide

Treat 4-(4-amino-5-(4-(1-isopropyl-4-pyridine-3) with 4 M HCl in 1,4-dioxane (1 mL) -yl)-1,4-dihydropyridin-3-methamide)phenyl)pyrrolo[1,2- f ][1,2,4]triazin-7-yl)piperidine-1- Suspension of tert-butyl formate (60 mg, 0.092 mmol) in _{CH2Cl2 (} 1 mL). The reaction mixture was stirred at room temperature for 2 h and concentrated to give a pale yellow solid, which was used directly in the next step. LCMS calculated for C ₃₁ H ₃₃ N ₈ O ₂ (M+H) ⁺ : m/z = 549.3. Experimental value: 549.3. Step 6 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -4- pendantoxy -5-( pyridin -3- yl )-1,4- dihydropyridine -3- methamide

Treat N -(4-(4 _- amino _- 7-(piperidin-4-yl))pyrrolo[1 ,2- f ][1,2,4]triazin-5-yl)phenyl)-1-isopropyl-4-side oxy-5-(pyridin-3-yl)-1,4-di Hydropyridine-3-carboxamide (20 mg, 0.036 mmol) and _Et3N (0.030 mL, 0.215 mmol) in _{CH2Cl2 (} 1 mL). The reaction mixture was stirred at room temperature for 40 min, quenched with saturated _NaHCO3 solution and extracted three times with EtOAc. The combined organic layers were dried over _Na2SO4 , concentrated and purified via pH 2 preparative LC/MS (MeCN/water with _TFA ) to yield the product as a cream solid (15 mg as TFA salt). LCMS calculated for C ₃₅ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 619.3. Experimental value: 619.3. Example 129. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-5-(5- fluoropyridin -3- yl )-1- isopropyl -4- sideoxy -1,4- dihydropyridine -3- methamide

Following a synthetic sequence similar to Example 128, using 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)pyridine in step 4 This compound was prepared instead of pyridin-3-ylboronic acid. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₅ H ₃₈ FN ₈ O ₃ (M+H) ⁺ : m/z = 637.3. Experimental value: 637.3. Example 130. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -6- methyl -2- sideoxy - 2H- [1,3'- bipyridyl ]-3- methamide Step 1 : 5- bromo -6- methyl -2- sideoxy -2H-[1,3'- bipyridine ]-3- carboxylic acid

5-Bromo-6-methyl-2-pendantoxy- 2H- [1,3'-bipyridyl]-3-carboxylic acid ethyl ester (570 mg, 1.69 mmol) (from Affinity Research Chemicals) and LiOH mono A mixture of hydrate (355 mg, 8.45 mmol) in MeOH (12 mL) and water (2.0 mL) was stirred at room temperature for 2 h and the MeOH was evaporated. Water was added to the residue and the resulting mixture was made slightly acidic by adding 1 N HCl, which resulted in the formation of a solid. The solid was collected by filtration, washed with water and dried to yield the product as a pink solid (333 mg, 64%). LCMS calculated for C ₁₂ H ₁₀ BrN ₂ O ₃ (M+H) ⁺ : m/z = 309.0. Experimental value: 309.0. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) Phenyl )-5- bromo -6- methyl -2- sideoxy -2H-[1,3'- bipyridyl ]-3- methamide

To 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (150 mg, 0.396 mmol) (Example 83, step 2) and 5-bromo-6-methyl-2-side oxy- 2H- [1,3' To a mixture of -bipyridyl]-3-carboxylic acid (123 mg, 0.396 mmol) in DMF (3.0 mL) was added _Et3N (0.083 mL, 0.594 mmol), followed by HATU (181 mg, 0.476 mmol). The resulting mixture was stirred at room temperature for 3 h, water was added and stirred for a further 15 min. The resulting solid was collected by filtration, washed with water and dried to yield product (250 mg, 94%). A portion of this material was further purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₃ H ₃₄ BrN ₈ O ₃ (M+H) ⁺ : m/z = 669.2. Experimental value: 669.2. ¹ H NMR (500 MHz, DMSO) δ 11.70 (s, 1H), 8.75 (dd, J = 4.8, 1.5 Hz, 1H), 8.67 (d, J = 2.2 Hz, 1H), 8.58 (s, 1H), 8.09 (s, 1H), 7.97 (ddd, J = 8.1, 2.4, 1.6 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.68 (dd, J = 7.9, 4.6 Hz, 1H), 7.45 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.53 (d, J = 12.8 Hz, 1H), 4.06 (d, J = 13.3 Hz, 1H), 3.49-3.32 (m, 1H) , 3.19 (t, J = 11.8 Hz, 1H), 2.98-2.79 (m, 1H), 2.68 (t, J = 11.5 Hz, 1H), 2.19 (s, 3H), 2.11-1.93 (m, 2H), 1.56 (dd, J = 59.6, 10.9 Hz, 2H), 1.00 (t, J = 6.8 Hz, 6H). Example 131. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) Phenyl )-5- chloro -6- methyl -2- sideoxy -2H-[1,3'- bipyridyl ]-3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (30 mg , 0.045 mmol) (Example 130, Step 2) A mixture of copper(I) chloride (13.3 mg, 0.134 mmol) in DMF (0.5 mL) was heated at 170 °C under microwave conditions and stirred for 12 min. The reaction mixture was cooled to room temperature, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₃ H ₃₄ ClN ₈ O ₃ (M+H) ⁺ : m/z = 625.2. Experimental value: 625.3. ¹ H NMR (600 MHz, DMSO) δ 11.73 (s, 1H), 8.76 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.12 (s, 1H), 7.98 (ddd, J = 8.1, 2.4, 1.5 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.69 (dd, J = 8.0, 4.8 Hz, 1H), 7.47 (d, J = 8.6 Hz, 2H), 6.77 (s, 1H), 4.53 (d, J = 11.8 Hz, 1H), 4.06 (d, J = 12.9 Hz, 1H), 3.41 (tt, J = 11.8, 3.5 Hz, 1H), 3.20 (t, J = 12.7 Hz, 1H), 2.89 (hept, J = 6.8 Hz, 1H), 2.68 (t, J = 11.9 Hz, 1H), 2.16 (s, 3H), 2.01 (dd, J = 29.4, 12.3 Hz, 2H) , 1.57 (dd, J = 73.5, 9.4 Hz, 2H), 1.01 (d, J = 6.9 Hz, 6H). Example 132. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5,6- dimethyl -2- sideoxy - 2H- [1,3'- bipyridyl ]-3- methamide

To N- (4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine under _N2 atmosphere -5-yl)phenyl)-5-bromo-6-methyl-2-sideoxy- 2H- [1,3'-bipyridyl]-3-methamide (30 mg, 0.045 mmol)( Example 130, step 2) and a mixture of PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.9 mg, 1.1 µmol) in 1,4-dioxane (0.50 mL) in toluene was added dropwise. 2.0 M dimethylzinc (0.086 mL, 0.172 mmol). The resulting mixture was stirred at 90°C overnight, cooled to room temperature, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₄ H ₃₇ N ₈ O ₃ (M+H) ⁺ : m/z = 605.3. Experimental value: 605.3. Example 133. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-(1- methyl - 1H - pyrazol -4- yl )-2- side oxy - 2H- [1,3'- bipyridyl ]-3- Formamide

In a sealed vial, add N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazine -5-yl)phenyl)-5-bromo-6-methyl-2-sideoxy- 2H- [1,3'-bipyridyl]-3-methamide (20 mg, 0.030 mmol)( Example 130, step 2), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -pyrazole ( A mixture of 12.4 mg, 0.060 mmol), Stir at 90 °C overnight under _N2 . The reaction mixture was then cooled to room temperature, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₇ H ₃₉ N ₁₀ O ₃ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.4. Example 134. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-(1- methyl - 1H - pyrazol -5- yl )-2- side oxy - 2H- [1,3'- bipyridyl ]-3- Formamide

According to a synthetic sequence similar to Example 133, 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H - was used This compound was prepared by substituting pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H -pyrazole. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₇ H ₃₉ N ₁₀ O ₃ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.4. Example 135. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-6- methyl -5-(1- methyl - 1H - pyrazol -3- yl )-2- side oxy - 2H- [1,3'- bipyridyl ]-3- Formamide

According to a synthetic sequence similar to Example 133, 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H - was used This compound was prepared by substituting pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboropentan-2-yl)-1 H -pyrazole. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₇ H ₃₉ N ₁₀ O ₃ (M+H) ⁺ : m/z = 671.3. Experimental value: 671.4. Example 136. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5- bromo -6-( methoxymethyl )-2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 5- Bromo -6-( bromomethyl )-2- side-oxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid ethyl ester

5-Bromo-6-methyl-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (310 mg, 0.92 mmol) (from Affinity Research Chemicals) and NBS ( To a mixture of carbon tetrachloride (6.0 mL)/chloroform (2.5 mL) was added 2,2'-azobis-isobutyronitrile (15.1 mg, 0.092 mmol). The resulting mixture was stirred at reflux for 6 h, cooled to room temperature and concentrated. The resulting material was purified via column chromatography (20% to 70% EtOAc in hexane) to yield the product as a yellow solid (234 mg, 61%). LCMS calculated for C ₁₅ H ₁₄ Br ₂ NO ₃ (M+H) ⁺ : m/z = 413.9. Experimental value: 414.0. Step 2 : 5- bromo -6-( methoxymethyl )-2- pendantoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

5-Bromo-6-(bromomethyl)-2-side oxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (100 mg, 0.24 mmol) and LiOH monohydrate ( A mixture of 50.5 mg, 1.21 mmol) in MeOH (4 mL) and water (0.7 mL) was stirred at room temperature for 1 h and the MeOH was evaporated. Water was added to the residue and the resulting mixture was made slightly acidic by adding 1 N HCl, which resulted in the formation of a solid. The solid was collected by filtration, washed with water and dried to yield the product as a yellow solid (79 mg, 97%). LCMS calculated for C ₁₄ H ₁₃ BrNO ₄ (M+H) ⁺ : m/z = 338.0. Experimental value: 338.0. Step 3 : 4-(4- amino -5-(4-(5- bromo -6-( methoxymethyl )-2- sideoxy -1- phenyl -1,2 - dihydropyridine- 3- Methylamido ) phenyl ) pyrrolo [1,2-f][1,2,4] triazin -7- yl ) piperidine -1- carboxylic acid tert-butyl ester

To 4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tertiary Butyl ester (95.0 mg, 0.23 mmol) (Example 107, step 4), 5-bromo-6-(methoxymethyl)-2-pentoxy-1-phenyl-1,2-dihydropyridine- To a solution of 3-formic acid (79 mg, 0.23 mmol) and _Et3N (0.049 mL, 0.349 mmol) in DMF (1.2 mL) was added HATU (106 mg, 0.28 mmol). The resulting mixture was stirred at room temperature for 2 h, water was added and stirred for a further 10 min. The resulting solid was collected by filtration, washed with water and dried to yield the product as a pale yellow solid (156 mg, 92%). LCMS calculated for C ₃₆ H ₃₉ BrN ₇ O ₅ (M+H) ⁺ : m/z = 728.2. Experimental value: 728.4. Step 4 : N-(4-(4- amino- 7-( piperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl ) -5- Bromo -6-( methoxymethyl )-2- side-oxy -1- phenyl -1,2- dihydropyridine -3- methamide dihydrochloride

To 4-(4-amino-5-(4-(5-bromo-6-(methoxymethyl)-2-sideoxy-1-phenyl-1,2-dihydropyridine-3- Formamido)phenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1-carboxylic acid tert-butyl ester (54 mg, 0.074 mmol) in CH To a solution of ₂ Cl ₂ (400 µL) was added 4 N HCl in 1,4-dioxane (148 µL, 0.59 mmol). The resulting mixture was stirred at room temperature for 2 h, concentrated and dried to give the product, which was used directly in the next step (50 mg, 96%). LCMS calculated for C ₃₁ H ₃₁ BrN ₇ O ₃ (M+H) ⁺ : m/z = 628.2. Experimental value: 628.3. Step 5 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl )-5- bromo -6-( methoxymethyl )-2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

To N -(4-(4-amino-7-(piperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)phenyl)-5 -Bromo-6-(methoxymethyl)-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-methamide dihydrochloride (20.0 mg, 0.029 mmol) and Et To a mixture of ₃ N (0.020 mL, 0.14 mmol) in CH ₂ Cl ₂ (0.40 mL) was added isobutyryl chloride (3.1 µL, 0.030 mmol). The resulting mixture was stirred at room temperature overnight, concentrated and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₅ H ₃₇ BrN ₇ O ₄ (M+H) ⁺ : m/z = 698.2. Experimental value: 698.2. ¹ H NMR (500 MHz, DMSO) δ 11.82 (s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.63-7.53 (m, 3H ), 7.45 (d, J = 8.6 Hz, 2H), 7.40 (d, J = 6.8 Hz, 2H), 6.69 (s, 1H), 4.53 (d, J = 12.7 Hz, 1H), 4.14 (s, 2H ), 4.05 (d, J = 13.8 Hz, 1H), 3.40 (t, J = 11.8 Hz, 1H), 3.18 (d, J = 12.9 Hz, 1H), 2.99 (s, 3H), 2.94-2.81 (m , 1H), 2.68 (t, J = 12.7 Hz, 1H), 2.10-1.95 (m, 2H), 1.56 (dd, J = 60.6, 9.7 Hz, 2H), 1.01 (d, J = 6.6 Hz, 6H) . Example 137. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-5- cyano -6-( ethoxymethyl )-2- pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide Step 1 : 5- Bromo -6-( ethoxymethyl )-2- sideoxy -1- phenyl -1,2- dihydropyridine -3- carboxylic acid

5-Bromo-6-(bromomethyl)-2-pendantoxy-1-phenyl-1,2-dihydropyridine-3-carboxylic acid ethyl ester (40 mg, 0.10 mmol) (Example 136, Step 1 ) and LiOH monohydrate (22 mg, 0.52 mmol) in EtOH (1.2 mL) and water (0.2 mL) was stirred at room temperature for 2 h and the EtOH was evaporated. Water was added to the residue and the resulting mixture was made slightly acidic by adding 1 N HCl, which resulted in the formation of a solid. The solid was collected by filtration, washed with water and dried to yield the product as a yellow solid (25 mg, 69%). LCMS calculated for C ₁₅ H ₁₅ BrNO ₄ (M+H) ⁺ : m/z = 352.0. Experimental value: 352.0. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-5- bromo -6-( ethoxymethyl )-2- sideoxy -1- phenyl -1,2- dihydropyridine -3- methamide

To 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (26 mg, 0.069 mmol) (Example 83, step 2) and 5-bromo-6-(ethoxymethyl)-2-pentoxy-1-benzene To a mixture of 1,2-dihydropyridine-3-carboxylic acid (24 mg, 0.069 mmol) in DMF (0.40 mL) was added Et ₃ N (0.014 mL, 0.10 mmol), followed by HATU (31 mg, 0.082 mmol). The resulting mixture was stirred at room temperature for 90 min, water was added and stirred for a further 10 min. The resulting solid was collected by filtration, washed with water and dried to yield the product as a pale yellow solid (47 mg, 96%). LCMS calculated for C ₃₆ H ₃₉ BrN ₇ O ₄ (M+H) ⁺ : m/z = 712.2. Experimental value: 712.2. Step 3 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-5- cyano -6-( ethoxymethyl )-2- pendantoxy -1- phenyl -1,2- dihydropyridine -3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (18.0 mg, 0.025 mmol), Pd A mixture of (OAc) ₂ (0.23 mg, 1.0 µmol), XantPhos (1.2 mg, 2.02 µmol), zinc cyanide (3.0 mg, 0.025 mmol) and TMEDA (1.1 µL, 7.6 µmol) in DMF (0.50 mL) was added. _N2 degassed and then heated at 160 °C and stirred under microwave conditions for 10 min. The reaction mixture was cooled to room temperature, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₇ H ₃₉ N ₈ O ₄ (M+H) ⁺ : m/z = 659.3. Experimental value: 659.3. ¹ H NMR (500 MHz, DMSO) δ 11.40 (s, 1H), 8.65 (s, 1H), 8.01 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.68-7.52 (m, 3H ), 7.50-7.38 (m, 4H), 6.67 (s, 1H), 4.51 (s, 1H), 4.22 (s, 2H), 4.04 (s, 1H), 3.40 (t, J = 11.7 Hz, 1H) , 3.31-3.12 (m, 3H), 2.95-2.82 (m, 1H), 2.65 (d, J = 26.7 Hz, 1H), 2.12-1.94 (m, 2H), 1.76-1.38 (m, 2H), 1.13 -0.88 (m, 9H). Example 138. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-3-(1,4- dimethyl - 1H - pyrazol -3- yl )-1- isopropyl -2,4- dilateral oxy -1,2,3,4- Ectoine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 87, using 1,4-dimethyl-1 H -pyrazol-3-amine instead of 1-methyl-1 H -pyrazol-4-amine. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₄ H ₄₁ N ₁₀ O ₄ (M+H) ⁺ : m/z = 653.3. Experimental value: 653.5. Example 139. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide Step 1 : Diethyl 2-(( cyclopropylamino ) methylene ) malonate

To a solution of diethyl 2-(ethoxymethylene)malonate (2.16 g, 10.0 mmol) in MeCN (20 mL) was added cyclopropylamine (0.70 mL, 10.1 mmol). The reaction mixture was stirred at room temperature overnight, then at 80 °C for 1 h, cooled to room temperature and concentrated to yield crude product, which was used directly in the next step. LCMS calculated for C ₁₁ H ₁₈ NO ₄ (M+H) ⁺ : m/z = 228.1. Experimental value: 228.1. Step 2 : 1- Cyclopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- carboxylate ethyl ester

A mixture of diethyl 2-((cyclopropylamino)methylene)malonate (0.45 g, 2.00 mmol) and isocyanoxybenzene (0.476 g, 4.00 mmol) in pyridine (0.97 mL) was stirred at 170 Heated and stirred at °C for 3 h, cooled to room temperature and purified via column chromatography (0% to 10% MeOH _{in CH2Cl2} ) to yield the product (0.336 g, 56%). LCMS calculated for C ₁₆ H ₁₇ N ₂ O ₄ (M+H) ⁺ : m/z = 301.1. Experimental value: 301.2. Step 3 : 1- cyclopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid

Ethyl 1-cyclopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (0.336 g, 1.12 mmol) was dissolved in 1,4- A mixture of 4.0 M HCl in dioxane (2.24 mL, 8.95 mmol) and water (0.56 mL) was stirred at 80 °C for 3 h, cooled to room temperature and concentrated to give crude product, which was used directly in the next step middle. LCMS calculated for C ₁₄ H ₁₃ N ₂ O ₄ (M+H) ⁺ : m/z = 273.1. Experimental value: 273.1. Step 4 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -2,4- bisoxy -3- phenyl -1,2,3,4- tetrahydropyrimidine -5- methamide

To 1-cyclopropyl-2,4-bisoxy-3-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (0.014 g, 0.050 mmol) and HATU (0.021 g, 0.055 mmol) in DMF (1 mL) was added 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4] Triazin-7-yl)piperidin-1-yl)-2-methylpropan-1-one (0.019 g, 0.050 mmol) (Example 83, step 2) and _Et3N (0.021 mL, 0.150 mmol). The reaction mixture was stirred at room temperature for 2 h, diluted with MeOH, adjusted to pH 2 with TFA and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₅ H ₃₇ N ₈ O ₄ (M+H) ⁺ : m/z = 633.3. Experimental value: 633.3. Example 140. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -2,4- bisoxy -3-( pyridin -3- yl )-1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 139, using 3-isocyanopyridine instead of isocyanoxybenzene in step 2. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₄ H ₃₆ N ₉ O ₄ (M+H) ⁺ : m/z = 634.3. Experimental value: 634.3. Example 141. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-1'- cyclopropyl -2'- methyl -4'- sideoxy -1',4'- dihydro- [2,3'- bipyridyl ]-5'- methamide Step 1 : 3-(( dimethylamino ) methylene )-6- methyl -2H- pyran -2,4(3H) -dione

To a solution of 6-methyl- 2H -piran-2,4( 3H )-dione (11.5 g, 91 mmol) in toluene (30 mL) was added N , N -dimethylformamide Dimethylacetal (13.1 mL, 98 mmol). The reaction mixture was then stirred overnight and concentrated to yield crude product, which was used directly in the next step. LCMS calculated for C ₉ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 182.1. Experimental value: 182.3. Step 2 : 1- Cyclopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

3-((Dimethylamino)methylene)-6-methyl- 2H -piran-2,4( 3H )-dione (1.92 g, 7.95 mmol), cyclopropylamine (0.83 mL, A mixture of sodium tert-butoxide (11.9 mmol) and sodium tert-butoxide (1.13 g, 11.8 mmol) in EtOH (5.0 mL) was heated at 90 °C and stirred for 18 h, cooled to room temperature, concentrated and treated with water and CH ₂ Cl ₂ . The aqueous solution was acidified with 4 N HCl and _extracted with _CH2Cl2 . The combined organic layers were washed with water, _brine , dried over _Na2SO4 and concentrated to give the desired compound (1.1 g, 42%). LCMS calculated for C ₁₀ H ₁₂ NO ₃ (M+H) ⁺ : m/z = 194.1. Experimental value: 194.3. Step 3 : 5- Bromo -1- cyclopropyl -6- methyl -4- sideoxy -1,4- dihydropyridine -3- carboxylic acid

1-Cyclopropyl-6-methyl-4-pendantoxy-1,4-dihydropyridine-3-carboxylic acid (0.83 g, 4.30 mmol) was treated with Br ₂ (0.29 mL, 5.58 mmol) in glacial acetic acid ( 6.0 mL). The reaction mixture was stirred at room temperature for 4 days, additional _Br2 (100 μL) was added and stirred overnight. The reaction mixture was diluted with water and the resulting solid was collected by filtration, washed with water and dried to give the product as a beige solid (1.0 g, 86% yield). LCMS calculated for C ₁₀ H ₁₁ BrNO ₃ (M+H) ⁺ : m/z = 272.0. Experimental value: 272.2. Step 4 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin- 5- yl ) phenyl )-5- bromo -1- cyclopropyl -6- methyl - 4- sideoxy -1,4- dihydropyridine -3- methamide

1-(4-(4-Amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (278 mg, 0.735 mmol) (Example 83, Step 2), 5-bromo-1-cyclopropyl-6-methyl-4-pendantoxy-1, A mixture of 4-dihydropyridine-3-carboxylic acid (200 mg, 0.735 mmol), HATU (335 mg, 0.882 mmol) and Et ₃ N (0.21 mL, 1.47 mmol) in DMF (5.0 mL) was stirred at room temperature. 2h and subsequent purification via column chromatography to yield product (252 mg, 54%). LCMS calculated for C ₃₁ H ₃₅ BrN ₇ O ₃ (M+H) ⁺ : m/z = 632.2. Experimental value: 632.3. Step 5 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1-f][1,2,4] triazin -5- yl ) phenyl )-1'- cyclopropyl -2'- methyl -4'- sideoxy -1',4'- dihydro- [2,3'- bipyridyl ]-5'- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (20.0 mg, 0.032 mmol) and 2-(tributyltin To a solution of alkyl)pyridine (11.3 mg, 0.032 mmol) in 1,4-dioxane (2.0 mL) was added Pd(Ph ₃ P) ₄ (7.3 mg, 6.3 µmol). The reaction mixture was heated and stirred at reflux overnight, cooled to room temperature and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₆ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 631.3. Experimental value: 631.1. ¹ H NMR (500 MHz, DMSO) δ 13.0-11.8 (m, 1H); 8.95 (m, 1H); 8.71 (s, 1H); 8.45 (m, 1H); 8.25 (s, 1H); 7.95-7.80 (m, 4H); 7.50 (m, 2H); 6.85 (m, 1H); 4.60 (m, 1H); 4.10 (m, 1H); 3.81 (m, 1H); 3.41 (m, 1H); 3.25 ( m, 1H); 2.85 (m, 1H); 2.65 (m, 1H); 2.41 (s, 3H); 2.1-1.9 (m, 2H); 1.7-1.4 (m, 2H); 1.3-1.1 (m, 4H); 1.0 (m, 6H). Example 142. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [2,1- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -2,2'- dimethyl -4- sideoxy -1,4- dihydro- [3,3'- bipyridyl ]-5- methamide

To (2-methylpyridin-3-yl)boronic acid (4.3 mg, 0.032 mmol) and N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1 ,2- f ][1,2,4]triazin-5-yl)phenyl)-5-bromo-1-cyclopropyl-6-methyl-4-sideoxy-1,4-dihydro To a solution of pyridine-3-methamide (20.0 mg, 0.032 mmol) (Example 141, step 4) in 1,4-dioxane (2.0 mL) and water (0.2 mL) was added K ₂ CO ₃ (26.0 mg, 0.188 mmol) and Pd(Ph ₃ P) ₄ (10.1 mg, 8.7 µmol). The reaction mixture was heated and stirred at reflux for 12 h, cooled to room temperature and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₇ H ₄₁ N ₈ O ₃ (M+H) ⁺ : m/z = 645.3. Experimental value: 645.1. Example 143. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -2,4- bisoxy -3-( pyrimidin -2- yl )-1,2,3,4 -tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 87, using pyrimidin-2-amine instead of 1-methyl- 1H -pyrazol-4-amine in step 1. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₃ H ₃₇ N ₁₀ O ₄ (M+H) ⁺ : m/z = 637.3. Experimental value: 637.3. ¹ H NMR (400 MHz, DMSO) δ 10.68 (s, 1H), 9.08 (d, J = 4.9 Hz, 2H), 8.73 (s, 1H), 8.08 (s, 1H), 7.84-7.72 (m, 3H ), 7.46 (d, J = 8.6 Hz, 2H), 6.75 (s, 1H), 4.76 (p, J = 6.7 Hz, 1H), 4.59-4.49 (m, 1H), 4.12-4.01 (m, 1H) , 3.49-3.34 (m, 1H), 3.27-3.14 (m, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.76-2.61 (m, 1H), 2.11-1.94 (m, 2H), 1.72 -1.49 (m, 2H), 1.45 (d, J = 6.8 Hz, 6H), 1.01 (s, 6H). Example 144. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -2,4- bisoxy -3-( pyridin -2- yl )-1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 139, using 2-isocyanopyridine instead of isocyanoxybenzene in step 2. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₄ H ₃₆ N ₉ O ₄ (M+H) ⁺ : m/z = 634.3. Experimental value: 634.3. ¹ H NMR (600 MHz, DMSO) δ 10.81 (s, 1H), 8.64 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 8.53 (s, 1H), 8.13-8.00 (m, 2H), 7.83 -7.74 (m, 2H), 7.56 (ddd, J = 7.5, 4.9, 1.0 Hz, 1H), 7.52 (dt, J = 8.0, 0.9 Hz, 1H), 7.49-7.41 (m, 2H), 6.73 (s , 1H), 4.54 (d, J = 12.2 Hz, 1H), 4.07 (d, J = 12.8 Hz, 1H), 3.41 (tt, J = 11.8, 3.6 Hz, 1H), 3.34-3.28 (m, 1H) , 3.20 (t, J = 12.3 Hz, 1H), 2.90 (p, J = 6.7 Hz, 1H), 2.69 (t, J = 12.0 Hz, 1H), 2.02 (dd, J = 30.8, 12.2 Hz, 2H) , 1.67-1.47 (m, 2H), 1.17-0.84 (m, 10H). Example 145. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) Phenyl )-3-(5- fluoropyridin -2- yl )-1- isopropyl -2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 87, using 5-fluoropyridin-2-amine instead of 1-methyl-1 H -pyrazol-4-amine in step 1. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₄ H ₃₇ FN ₉ O ₄ (M+H) ⁺ : m/z = 654.3. Experimental value: 654.3. Example 146. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -4- pendantoxy -5-( pyridin -2- yl )-1,4- dihydropyridine -3- methamide Step 1 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-5- bromo -1- isopropyl -4- sideoxy -1,4- dihydropyridine -3- methamide

To 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[2,1- f ][1,2,4]triazin-7-yl)piperidine-1- methyl)-2-methylpropan-1-one (200 mg, 0.53 mmol) (Example 83, step 2) and 5-bromo-1-isopropyl-4-pentoxy-1,4-dihydropyridine To a mixture of -3-carboxylic acid (137 mg, 0.53 mmol) (Example 128, Step 2) in DMF (4.0 mL) was added _Et3N (0.11 mL, 0.79 mmol) followed by HATU (241 mg, 0.63 mmol) . The resulting mixture was stirred at room temperature for 3 h, water was added and stirred for a further 15 min. The resulting solid was collected by filtration, washed with water and dried to yield the product. LCMS calculated for C ₃₀ H ₃₅ BrN ₇ O ₃ (M+H) ⁺ : m/z = 620.2. Experimental value: 620.2. Step 2 : N-(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2-f][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -4- pendantoxy -5-( pyridin -2- yl )-1,4- dihydropyridine -3- methamide

To N -(4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (40.0 mg, 0.064 mmol), Pd(PPh ₃ ) ₄ (14.9 mg, To a mixture of 0.013 mmol) in toluene (1.2 mL) was added 2-(tributylstannyl)pyridine (0.042 mL, 0.129 mmol). The mixture was purged with _N2 and heated at 120 °C with stirring overnight. The reaction mixture was then cooled to room temperature, diluted with MeOH, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₅ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 619.3. Experimental value: 619.3. Example 147. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- cyclopropyl -6- methyl -4- pendantoxy -5-( pyridin -3- yl )-1,4- dihydropyridine -3- methamide

N -(4-(4-Amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[2,1- f ][1,2,4]triazin-5-yl)benzene (12.0 mg, 0.019 mmol) (Example 141, Step 4) ), pyridin-3-ylboronic acid (2.8 mg, 0.023 mmol), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) (2 '-Amino-1,1'-biphenyl-2-yl)palladium(II) (Xphos Pd G2) (1.5 mg, 1.90 µmol) and tripotassium phosphate (8.9 mg, 0.042 mmol) in 1,4-di A mixture of oxane (0.50 mL) and water (0.10 mL) was degassed with _N2 and then heated at 80 °C and stirred for 2 h. The reaction mixture was then cooled to room temperature, diluted with MeOH, filtered and purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as a TFA salt. LCMS calculated for C ₃₆ H ₃₉ N ₈ O ₃ (M+H) ⁺ : m/z = 631.3. Experimental value: 631.3. Example 148. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-3-(1,5- dimethyl - 1H - pyrazol -3- yl )-1- isopropyl -2,4- di-oxy -1,2,3,4- Ectoine -5- methamide

This compound was prepared according to a synthetic sequence similar to Example 87, using 1,5-dimethyl-1 H -pyrazol-3-amine instead of 1-methyl-1 H -pyrazol-4-amine in step 1 . This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₄ H ₄₁ N ₁₀ O ₄ (M+H) ⁺ : m/z = 653.3. Experimental value: 653.3. Example 149. N -(4-(4- amino- 7-(1- isobutyrylpiperidin -4- yl ) pyrrolo [1,2- f ][1,2,4] triazin- 5- yl ) phenyl )-1- isopropyl -3-(6- methylpyridin -2- yl )-2,4- bisoxy -1,2,3,4- tetrahydropyrimidine -5- carboxylic acid amine

This compound was prepared according to a synthetic sequence similar to Example 87, using 6-methylpyridin-2-amine instead of 1-methyl- 1H -pyrazol-4-amine in step 1. This compound was purified via pH 2 preparative LC/MS (MeCN/water with TFA) to yield the product as the TFA salt. LCMS calculated for C ₃₅ H ₄₀ N ₉ O ₄ (M+H) ⁺ : m/z = 650.3. Experimental value: 650.3. Example A Axl Autophosphorylation Assay

By incubating recombinant Axl protein (Life Technologies, PV4275) in buffer containing 50 mM Tris (pH7.5), 0.2 mg/ml Axl, 5 mM ATP, ₂₀ mM MgCl and 2 mM DTT at room temperature. Autophosphorylation of Axl was performed for 1 hour. TAM enzyme analysis

Kinase assay buffer contains 50 mM HEPES (pH7.5), 10 mM MgCl2, 1 mM EGTA, 0.01% NP-40, and 2 mM DTT. Transfer 0.1 ul of test compound dissolved in DMSO from the compound plate to a white 384-well assay plate (Greiner LUMITRAC plate). The final concentration of DMSO is 1.25%. Enzyme solutions of 5.1 nM Phospho-Axl or 0.0625 nM c-Mer (Carna Biosciences, 08-108) or 0.366 nM Tyro3 (Life Technologies, PR7480A) were prepared in assay buffer. A 1 mM stock solution of the peptide substrate biotin-EQEDEPEGDYFEWLE-amide SEQ ID NO: 1 (Quality Controlled Biochemicals, MA) in DMSO was diluted to 1 uM in assay buffer containing 2000 uM ATP. Add 4 ul of enzyme solution (or assay buffer for enzyme blanks) to the appropriate wells of each culture plate, and then add 4 ul of substrate solution per well to initiate the reaction. Protect the plate from light and incubate at room temperature for 60 min. By adding 4 ul of anti- The reaction was stopped with a detection solution of phosphotyrosine PY20 (Perkin Elmer, AD0067). The culture plate was incubated at room temperature for 1 h, and the HTRF (homogenous time resolved fluorescence) signal was measured on a PHERAstar FS culture plate reader (BMG labtech). The percent inhibition for each concentration was calculated and IC50 values were generated from curve fitting with GraphPad Prism software.

According to TAM enzyme analysis, these compounds were found to be inhibitors of TAM. All compounds as described herein have been tested. The compounds shown in Table 1 below exhibit an _IC50 of less than 1 µM against at least one kinase selected from Tyro3, Axl and Mer.

Compounds provided herein are found to be inhibitors of one or more of AXL, MER and TYRO3. IC ₅₀ data is provided in Table 1 below. The symbol “” indicates IC ₅₀ ≤ 5 nM, and “” indicates IC ₅₀ >5 nM but ≤ 10 nM. “” means IC ₅₀ ＞10 nM but ≤ 100 nM; “” means IC ₅₀ is greater than 100 nM; and na means not available. Table 1 Example Axl IC ₅₀ (nM) Mer IC ₅₀ (nM) Tyro3 IC ₅₀ (nM) 1    2    3    4    5    7 (cis isomer)  †  7 (trans isomer) † †  8    9    10    11    12  †  13    14 † †  15 † †  16 † †  17 † †  18 † †  19 † † † 20    twenty one  †  twenty two † †  twenty three † †  twenty four † †  25 † †  26 † †  27 † †  28 † †  29 † †  30 † †  31 † †  32 † †  33 † †  34 † †  35 † †  36    37 † †  38 † †  39 † †  40    41 † †  42 † †  43 † †  44 † †  45 † †  46 † †  47 † †  48    49 † †  50 † †  51 † †  52 † †  53  †  54 † †  55 † †  56    57 †   58 †   59 †   60 †   61 † †  62 † †  63 † †  64 † †  65 † †  66 †   67 † †  68 † †  69 †   70 † †  71 †   72 †   73 †   74 † †  75 † †  76 †   77 †   78 † †  79 † †  80 †   81 † †  82 † †  83 † †  84    85 †   86    87 † †  88 † †  89 na na na 90    91 †   92 na na na 93 † † † 94 †   95 †   96 † †  97 †   98 † †  99 † †  100    101 † †  102 † †  103 † †  104 † †  105 †   106 † †  107 †   108 † †  109 † †  110 †   111 † †  111a    112 † †  113 † †  114 † †  115 †   116 † †  117 †   118 † †  119 † †  120 † †  121 † †  122 † †  123 †   124 †   125 † †  126 † †  127 † †  128 †   129 †   130 † †  131 † †  132 † †  133 †   134 †   135 † †  136 † †  137 †   138 †   139 † †  140 †   141 † †  142 †   143 †   144 †   145 na na na 146 na na na 147 † †  148 †   149 †   Example B. Generation of BAF3-AXL , BAF3-MER and BAF3-TYRO3 cells and analysis of cell proliferation

The cytoplasmic domain of AXL, MER or TYRO3 fused to the dimerization sequence and HA tag was cloned into the pMSCV vector with a puromycin resistance marker to generate three constructs (pMSCV-AXL, pMSCV-MER and pMSCV-TYRO3 ). BAF3 cells were individually transfected with the three constructs by electroporation. A single pure line with IL3 independence and puromycin resistance was selected and characterized. Cells with stable expression of AXL, MER or TYRO3 were selected and represented as BAF3-AXL, BAF3-MER and BAF3-TYRO3 cells.

BAF3, BAF3-AXL, BAF3-MER, or BAF3-TYRO3 cell lines were maintained in RPMI1640 (Gibco/Life Technologies, Carlsbad, CA) with 10% FBS. To measure the effect of test compounds on cell viability, 1000 cells per well were plated in 384-well tissue culture dishes in growth medium and _serially diluted with compound alone or DMSO at 37°C with 5% CO for 48 hours. , cell viability was measured by ATP assay (CellTiter-Glo Assay, Promega) according to the manufacturer's procedure. Data were converted to percent inhibition relative to DMSO control and _IC50 curves were fitted using GraphPad Prism software. Example C. BaF3-AXL ELISA and BaF3-MER ELISA

BaF3-AXL or BaF3-MER cells were maintained in medium RPMI (1 µg/ml, Gibco/Life Technologies, Carlsbad, CA) with 10% FBS and puromycin. To measure the effect of test compounds on phospho-AXL or phospho-MER, cells were plated (5 × ¹⁰ cells per well) on V-bottomed polymers in the presence or absence of test compounds diluted in culture medium. Acrylic culture plates (Greiner bio-one) and incubated at 37°C with 5% _CO2 for 1 hour. Cells were harvested by centrifugation and lysed in 110 µl of ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher) on ice for 30 min. Cell lysates were stored at -80°C for ELISA. Prepare ELISA plates by incubating Costar plates with anti-HA antibody (1 µg/ml) for 1 hour at room temperature. The culture plates were washed and blocked with PBS with 3% BSA. Cell lysates were loaded onto ELISA plates and incubated at 4°C overnight. The plates were washed and incubated for 1 hour with LANCE Eu-W1024 anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) and read on a Pherastar (BMG Labtech) . Data were converted to percent inhibition relative to DMSO control and _IC50 determinations were performed by fitting a curve of percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism. Example D. H1299 Phosphorus -AXL ELISA

H1299 cells (ATCC), a human non-small cell lung cancer cell line with Axl expression, were maintained in medium RPMI (Gibco/Life Technologies, Carlsbad, CA) with 10% FBS. To measure the effect of test compounds on phospho-AXL, cells were plated (30,000 cells per well) in 96-well tissue culture plates (Costar) and incubated overnight at 37°C with 5% _CO2 . Compounds were added at appropriate concentrations and incubated for 1 hour at 37°C with 5% _CO2 . Add rhGas6 (R&D Systems, 6 µg/ml) to each well. Incubate the culture plate at 37°C with 5% _CO for 15 min. Cells were harvested and lysed in 110 µL of ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher). Lysates were incubated on ice for 1 hour and stored at -80°C for ELISA. Prepare ELISA plates by incubating Costar plates with anti-HA antibody (1 µg/ml) for 1 hour at room temperature. The culture plates were washed and blocked with PBS with 3% BSA. Cell lysates were loaded onto ELISA plates and incubated at 4°C overnight. The plates were washed and incubated for 1 hour with LANCE Eu-W1024 anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) and read on a Pherastar (BMG Labtech) . Data were converted to percent inhibition relative to DMSO control and _IC50 determinations were performed by fitting a curve of percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism. Example E. Whole Blood H1299 Phosphorus -AXL ELISA

H1299 cells (ATCC) were maintained in medium RPMI (Gibco/Life Technologies, Carlsbad, CA) with 10% FBS. To measure the effect of test compounds on phospho-AXL in whole blood, cells were plated (30,000 cells per well) in 96-well tissue culture plates (Costar) and incubated overnight at 37°C with 5% _CO2 . Blood obtained from normal donors was mixed with the test compound for 1 hour. Medium was removed from H1299 cells and blood with compound was added to each well. After incubation for 1 h at 37°C with 5% _CO2 , rh-Gas6 (4 µg/ml, R&D Systems) was added to each well. Incubate the culture plate at 37°C with 5% _CO for 15 min. Cells were washed with PBS and lysed in 110 uL of ice-cold lysis buffer (Cell Signaling) with protease and phosphatase inhibitors (Halts PI, Thermo Fisher) on ice for 1 hour. Culture plates were stored at -80°C for ELISA. Prepare ELISA plates by incubating Costar plates with anti-HA antibody (1 µg/ml) for 1 hour at room temperature. The plates were washed and incubated for 1 hour with LANCE Eu-W1024 anti-phospho-tyrosine antibody (PY-20) (Perkin Elmer) in DELFIA assay buffer (Perkin Elmer) and read on a Pherastar (BMG Labtech) . Data were converted to percent inhibition relative to DMSO control and _IC50 determinations were performed by fitting a curve of percent inhibition versus logarithm of inhibitor concentration using GraphPad Prism. Example F. G361 Phospho -Akt Cell Insight ELISA

G361 cells (ATCC), a Mer-expressing human malignant melanoma cell line, were maintained in medium RPMI (Gibco/Life Technologies, Carlsbad, CA) with 10% FBS. To measure the effect of test compounds on the MER signal transduction pathway, cells were plated in 96-well CellBind surface culture plates (Corning) at 2 × 10 ⁴ cells per well in 100 µL volume and incubated at 37°C with 5% CO ₂ Grow overnight. Add 20 µL of the appropriate concentration of test compound to the cells and incubate for 1 hour. rhGas6 (4 µg/ml, R&D Systems) was added to each well and incubated for 20 min. Cells were fixed by adding 50 uL of 4% polyformaldehyde (Electron Microscopy Sciences) in PBS (Corning) for 30 min at room temperature. The culture plates were washed and incubated with 50 uL of 0.2% Tritium X-100 (Sigma) in PBS for 10 minutes at room temperature. The culture plate was washed and incubated with 100uL blocking buffer (0.1% BSA in PBS) for 30 min. The plates were washed and incubated overnight at 4°C with phospho-AKT (Ser473) (D9E) rabbit mAb (Cell Signaling) diluted in 0.1% BSA (1:300 dilution). Wash the plate and incubate with 50uL of goat anti-rabbit IgG (H+L) (Molecular Probes, 1:1000 dilution) and Hoechst 33342 (Thermo Fisher, 1:2000 dilution) Alexaflour 488 F (ab) in PBS at room temperature. ') ² fragments were incubated for 2 hours. The plates were washed with PBS and read on a Cell Insight CX5 (Thermo Fisher).

Various modifications to the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to be within the scope of the accompanying patent application. Each reference cited in this application, including all patents, patent applications, and publications, is hereby incorporated by reference in its entirety.

         <![CDATA[<110> Incyte Corporation]]>
          <![CDATA[<120> Pyrrotriazine compounds as TAM inhibitors]]>
          <![CDATA[<130> TW 106110194]]>
          <![CDATA[<150> US 62/438,750]]>
          <![CDATA[<151> 2016-12-23]]>
          <![CDATA[<150> US 62/362,934]]>
          <![CDATA[<151> 2016-07-15]]>
          <![CDATA[<150> US 62/314,066]]>
          <![CDATA[<151> 2016-03-28]]>
          <![CDATA[<160> 1 ]]>
          <![CDATA[<170> PatentIn version 3.5]]>
          <![CDATA[<210> 1]]>
          <![CDATA[<211> 15]]>
          <![CDATA[<212> PRT]]>
          <![CDATA[<213> artificial sequence]]>
          <![CDATA[<220>]]>
          <![CDATA[<223> Synthetic peptide]]>
          <![CDATA[<400> 1]]>
          Glu Gln Glu Asp Glu Pro Glu Gly Asp Tyr Phe Glu Trp Leu Glu
          1 5 10 15
          
      

Claims (5)

A compound is used to prepare a drug for treating cancer. The compound is N- (4-(4-amino-7-(1-isobutyrylpiperidin-4-yl)pyrrolo[1,2- f ][ 1,2,4]triazin-5-yl)phenyl)-1-isopropyl-2,4-bisoxy-3-(pyridin-2-yl)-1,2,3,4- Ectoine-5-methamide or a pharmaceutically acceptable salt thereof, wherein the drug further contains one or more additional therapeutic agents, or is used in combination with one or more additional therapeutic agents, wherein: a) the one or a plurality of additional therapeutic agents selected from antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressive agents, radiation, antitumor or antiviral vaccines, cytokine therapy, and tyrosine kinase inhibitors; or b) The one or more additional therapeutic agents are inhibitors of immune checkpoint molecules selected from the group consisting of anti-PD1 antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies. The use of claim 1, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, Prostate cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, thyroid cancer, skin cancer, leukemia, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, acute myeloid leukemia, Hodgkin's Hodgkin's lymphoma or non-Hodgkin's lymphoma, Waldenstrom's Macroglubulinemia, pilocytic lymphoma, Burkett's lymphoma, glial blastoma, melanoma and rhabdomyosarcoma. Such as the use of claim 1, wherein the cancer is lung cancer, prostate cancer, colon cancer, breast cancer, melanoma tumor, renal cell carcinoma, multiple myeloma, gastric cancer, or rhabdomyosarcoma. Such as the use of claim 1, wherein the one or more therapeutic agents are selected from antiviral agents, chemotherapeutic agents or other anticancer agents, immune enhancers, immunosuppressive agents, radiation, antitumor or antiviral vaccines, and cytokine therapy and tyrosine kinase inhibitors. The use of claim 1, wherein the one or more therapeutic agents are inhibitors of immune checkpoint molecules selected from the group consisting of anti-PD1 antibodies, anti-PD-L1 antibodies and anti-CTLA-4 antibodies.